Reviewed by Dr. Neil Keshvani
Khanna A, et al. NEJM. 2017 Aug 377(5):419-430

SUMMARY
ATHOS-3, or Angiotensin II for the Treatment of High-Output Shock, is a phase 3 multinational, randomized, double-blind, placebo-controlled trial to determine whether the addition of angiotensin II to conventional vasopressors improves blood pressure in patients with catecholamine-resistant vasodilatory shock. The study population included patients with vasodilatory shock despite treatment with 25 ml/kg of IV volume resuscitation and concurrent administration of norepinephrine > 0.2 μg/kg/min or equivalent dose of another vasopressor for at least 6 hours but not longer than 48 hours. Vasodilatory shock was measured as a cardiac index > 2.3 with a mixed venous O2 saturation > 70% and a central venous pressure (CVP) > 8. The medication was initially administered over three hours and uptitrated to increase the MAP to at least 75 mm Hg (dose 1.25 – 40 ng/kg/min). During this initiation, standard doses of background vasopressors were held constant. If these doses were increased for safety reasons, patients were marked as non-responders. At hour 48, the study infusion was discontinued according to a protocoled tapering process. The primary end point was the change in mean arterial pressure (MAP) at hour 3, with response defined as a MAP of 75 mm Hg or higher or an increase in 10 mm Hg from baseline. Secondary outcomes were change in both cardiovascular and total SOFA scores, and safety outcomes were all-cause mortality at both 7 and 28 days.

The study regimen was initiated on 321 patients – 163 received angiotensin II and 158 received placebo. 69.9% of patients in the angiotensin II group met the primary end point versus only 23.4% of patients in the placebo group (p<0.001, OR 7.95, CI 4.76-13.3). The most common causes of treatment failure included failure to meet blood pressure goals and an increase in the dose of background vasopressors. A MAP increase of 12.5 mm Hg was achieved in the angiotensin II group at 3 hours, versus an increase of 2.9 mm Hg in the placebo arm (p<0.001). This led to a lower dose of background vasopressor use during the first 48 hours in the angiotensin II group versus placebo (article Fig. 2). However, there were no significant differences in the total SOFA score between the two groups (p=0.49). Additionally, death from any cause by day 28 occurred in 46% of patients in the angiotensin II group and in 53.8% of the placebo group (p=0.12). Importantly, safety data were similar between placebo and angiotensin II, with no differences in the rates of atrial fibrillation, digital ischemia, or ventricular tachycardia.

COMMENTARY
This Phase 3 trial is an important stepping stone in the investigation of angiotensin II as a possible vasopressor in vasodilatory shock, of which sepsis is the most common clinical etiology. It showed that angiotensin II had a significant impact on blood pressure compared to placebo, supporting previously published data from phase II trials.1 While administration of angiotensin II did not have a measurable effect on mortality, this study was not powered to measure this outcome. Furthermore, mortality data is lacking with many of the currently used vasopressors, and there are real questions as to whether mortality improvements are necessary before clinical use.

Angiotensin II did not have any detectable patient safety concerns, although the small sample size and relatively short duration of monitoring (28-days) cannot preclude the possibility of important side effects. However, this study excluded patients with a low cardiac output. Vasoconstriction can result in a further reduction in cardiac output, and therefore this vasopressor could potentially cause severe harm in patients with cardiogenic shock. Further trials should include a larger sample size and a longer duration of follow-up to further evaluate more long-term adverse effects. This trial presents convincing data as a proof of concept, however, before consideration of clinical use, more investigation is required.

REFERENCES
1. Chawla LS, Busse L, Brasha-Mitchell E, et al. Intravenous angiotensin II for the treatment of high-output shock (ATHOS trial): a pilot study. Crit Care. 2014;18(5):534.

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