Does the addition of angiotensin II improve blood pressure in patients with vasodilatory shock that is resistant to high-dose vasopressors?

In this industry-sponsored trial, angiotensin II improved blood pressure and allowed for decreased doses of vasopressor without increasing adverse events or mortality in patients with vasodilatory shock. (LOE = 1b)

Khanna A, English SW, Xueyuan SW, et al, for the ATHOS-3 Investigators. Angiotensin II for the treatment of vasodilatory shock. N Engl J Med 2017;377(5):419-430.  [PMID:28528561]

Randomized controlled trial (double-blinded)

Industry

Concealed

Inpatient (ICU only)

In this Phase III trial, investigators randomized adult patients with vasodilatory shock resistant to intravenous volume resuscitation and high-dose vasopressors (norepinephrine 0.2 mcg/kg/min or equivalent) to receive either synthetic human angiotensin II (n = 163) or placebo (n = 158). Patients with extensive burns, acute coronary syndrome, liver failure, active bleeding, and neutropenia were excluded. Angiotensin II was infused at a starting rate of 20 ng/kg/min and was adjusted during the first 3 hours to increase the mean arterial pressure (MAP) to 75 mm Hg or higher. Background vasopressors were continued but doses could not be increased for the first 3 hours and 15 minutes. If the doses were increased, the patient was categorized as not having had a response to the study intervention. After 48 hours, the study medication was stopped but could be restarted for up to 7 days if maximum doses of vasopressors were required or if the patient became unstable. Once the study medication was stopped for more than 3 hours, however, it could not be resumed. The 2 groups were similar, with a median age of 64 years and a median baseline MAP of 66.3 mm Hg. Approximately, 80% of patients in each group had septic shock. The primary outcome was a response to the study drug indicated by a MAP of 75 mm Hg or higher or an increase in MAP of at least 10 mm Hg at 3 hours. This occurred more frequently in the angiotensin II group than in the placebo group (69.9% response vs 23.4% response; P < .001; number needed to treat = 2). The angiotensin II group also had a greater increase in MAP overall during the first 3 hours (12.5 mm Hg vs 2.9 mm Hg; P < .001) and used lower doses of background vasopressors during the first 48 hours. There were no differences in adverse events between the 2 groups, including events that could be related to the study medication, such as arrhythmias and digital ischemia. Additionally, angiotensin II did not lead to higher mortality at day 7 or day 28, although the trial was not powered to detect changes in mortality.