Table 2.

Number of patients, sub-populations, outcomes and main limitations of the secondary analysis of ATHOS-3 clinical trial

Title	Patients	Population	Primary outcomes	Other Results	Main Limitiations
Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II (Tumlin JA et al. Crit Care Med 2018)	105	Subgroups of ATHOS-3, patients who need RRT at the time of study drug initiation, Placebo (n = 60) Ang II ( n = 45)	Difference in 28-day survival between Ang II and placebo groups was 53% vs 30% respectively; unadjusted hazard ratio 0.52; 95% CI, [0.30–0.87] (p = 0.012)	Day 7 alive and ventilator-free between Ang II and placebo groups was 30,2% vs 10,7% respectively; hazard ratio 3.14 [1.19–8.26] (p value = 0.015) Day 7 alive and renal replacement therapy-free between Ang II and placebo groups was 38% vs 15% respectively; hazard ratio, 2.90 [1.29–6.52] (p value = 0.007)	Volume status was not analyzed in this post hoc analysis, and the absence of a premorbid serum creatinine precludes any analysis of the impact of preexisting chronic kidney disease
Outcomes in patients with acute respiratory distress syndrome receiving angiotensin II for vasodilatory shock (Busse L et al. Critical Care 2018)	321	Subgroup of ATHOS-3, patients with moderate and severe acute ARDS. Placebo n = 158: 32% mild ARDS, 32% moderate ARDS, 12% severe ARDS); Ang II n = 163: 34% mild ARDS, 30% moderate ARDS, 11% severe ARDS	Mean arterial pressure response was achieved by 24%, 25%, and 16% of patients in the placebo group and 67% (OR = 6.7, p < 0.001), 69% (OR = 6.6, p < 0.001), and 61% (OR = 8.4, p = 0.005) in the Ang II group for mild, moderate and severe ARDS respectively	28-day mortality between placebo and Ang II groups related to ARDS severity. Placebo: Mild 53 [40–67] Moderate 55 [42–69] Severe 74 [53—90]; Ang II Mild 42 [30–56] Moderate 55 [42–69] Severe 50 [30–74]	NA
Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock: A Clinical Trial. (Bellomo R et al. Am J Respir Crit Care Med. 2020)	255	Subgroup of ATHOS-3, patients with serum samples available for analysis of renin concentrations at baseline Renin below the median population value (< 172.7 pg/ml) n = 127, placebo 63; Ang II 64; Renin above the median population value (> 172.7 pg/ml) n = 128. placebo 73; Ang II 55)	28-day mortality rate between placebo and Ang II in patients with renin concentration above the median was 69.9% vs 51.1% respectively, hazard ratio, 0.556 [95% CI, 0.35–0.88] (p = 0.0115). There was no statistically significant difference in 28-day mortality for those with serum renin concentrations below median	In patients with renin concentration above the median the rate of renal replacement therapy liberation by Day 7 was: Ang II 43% vs placebo 12% (p = 0.01). The mean change in cardiovascular SOFA score at 48 h was significantly greater in the Ang II group (- 1.56 ± 1.79) vs placebo group (- 0.78 ± 1.39) There was no statistically significant difference for those with serum renin concentrations below median	No measure of angiotensin 1–7, bradykinin, or aldosterone concentrations,. No rigorously assess for the presence or severity of preexisting hypertension, renovascular disease, or chronic kidney disease
Initiating angiotensin II at lower vasopressor doses in vasodilatory shock: an exploratory post-hoc analysis of the ATHOS-3 clinical trial (Wieruszewski et al. Crit Care 2023)	321	Subgroups of ATHOS-3, Low NED (≤ 0.25 μg/kg/min; n = 104. placebo 48; ANGII 56); High NED (> 0.25 μg/kg/min; n = 217. placebo 110; ANGII 107)	Difference in 28-day survival between the Ang II and placebo in NED ≤ 0.25 μg/kg/min: 64% vs 48% (p 0.03); NED > 0.25 μg/kg/min: 49% vs 45%; (p 0.71)	Difference in incidence of discontinuing RRT at day 7 between Ang II and placebo in NED ≤ 0.25 μg/kg/min 59% vs 33% (p = 0.29); NED > 0.25 μg/kg/min 29% vs 11% (p = 0.03)	The study design resulted in only one third of patients being enrolled at NED ≤ 0.25 μg/ kg/min, limiting the generalizability of these data. It is possible that low-NED and high-NED do not correlate with early or late stage of disease

Ang II: angiotensin II; ARDS Acute respiratory distress syndrome, NED norepinephrine dose equivalent