Role of angiotensin II in treatment of refractory distributive shock

Objective. Clinical data and gaps in knowledge regarding angiotensin II (AT(2)), 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. AT(2) 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 It was previously available but withdrawn from the US market; previous low-quality research describes increases in mean arterial pressure (MAP).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 AT(2) was based on data from a Phase III randomized trial comparing i.v. AT(2) (n = 163) with placebo use (n = 158) in patients with vasodilatory shock receiving high doses of other vasopressors. AT(2) 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 AT(2) and placebo recipients, respectively, including venous and arterial thromboembolic events (12.9% [n = 21] and 5.1% [n = 8], respectively). No significant effects of AT(2) on 7- or 28-day mortality were seen among all patients in the ATHOS-3 trial. However, post hoc analyses suggested that AT(2) may reduce mortality in patients with low baseline AT(2) levels, exaggerated response to AT(2), 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 AT(2) for vasodilatory shock cannot be determined with confidence. Conclusion. Intravenous AT(2) 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.