Role of angiotensin II in treatment of refractory distributive shock.

Objective: Clinical data and gaps in knowledge regarding angiotensin II (AT2), which was approved by the Food and Drug Administration in December 2017 via priority review for treatment of septic and other vasodilatory shock, is discussed.

Summary: AT2 is an endogenous peptide that raises blood pressure via vasoconstriction and increased aldosterone release. It was previously available but withdrawn from the US market; previous low-quality research describes increases in mean arterial pressure (MAP). The recent approval of AT2 was based on data from a Phase III randomized trial comparing i.v. AT2 (n = 163) with placebo use (n = 158) in patients with vasodilatory shock receiving high doses of other vasopressors. AT2 significantly increased achievement of the primary endpoint, MAP response at 3 hours after the start of infusion, relative to placebo use (69.9% [n = 114] versus 23.4% [n = 37], p < 0.0001). Serious adverse events occurred in 60.7% (n = 99) and 67.1% (n = 106) of patients treated with AT2 and placebo recipients, respectively, including venous and arterial thromboembolic events (12.9% [n = 21] and 5.1% [n = 8], respectively). No significant effects of AT2 on 7- or 28-day mortality were seen among all patients in the ATHOS-3 trial. However, post hoc analyses suggested that AT2 may reduce mortality in patients with low baseline AT2 levels, exaggerated response to AT2, and acute kidney injury receiving concomitant renal replacement therapy. Overall, due to shortcomings of the ATHOS-3 trial data and the absence of confirmatory studies, the optimal place in therapy of AT2 for vasodilatory shock cannot be determined with confidence.

Conclusion: Intravenous AT2 represents a novel treatment strategy for refractory septic or other vasodilatory shock, although findings of safety and efficacy have not been replicated and the drug's optimal place in therapy is uncertain.