FDA Approval of Angiotensin II for the Treatment of Hypotension in Adults with Distributive Shock

Abstract

Distributive shock is a subset of shock marked by decreased systemic vascular resistance, organ hypoperfusion and altered oxygen extraction. Despite the use of intravenous fluids and either higher dose of catecholamines or other additional exogenous vasopressors to maintain blood pressure in the target range, the rate of mortality remains higher in patients with septic shock. Therefore, there is clearly an unmet need for additional safe and effective treatments. The use of angiotensin II to raise the mean arterial pressure (MAP) could provide additional therapy and the opportunity to evaluate a catecholamine-sparing effect by decreasing the dose of concomitant catecholamines while maintaining a target MAP. ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock phase 3; ClinicalTrials.gov number, NCT02338843) was an adequate and well-controlled trial. The primary endpoint was the rate of MAP response at hour 3 of treatment with study drug, defined as either a 10-mmHg increase from baseline in MAP or a MAP of at least 75 mmHg. The secondary endpoints were changes from baseline in Sequential Organ Failure Assessment (SOFA) scores (total and cardiovascular). Mortality was an exploratory endpoint. The trial provided substantial evidence of the effectiveness of angiotensin II in raising blood pressure over placebo in patients with distributive shock, while keeping catecholamine levels constant. There was no change in the secondary endpoint of total SOFA scores relative to placebo when catecholamine use was reduced in lieu of angiotensin II treatment. There was a slight decrease in the secondary endpoint of cardiovascular SOFA score relative to placebo during the catecholamine-sparing phase, reflecting the catecholamine-sparing effect. There was a consistent trend in decreased mortality relative to placebo over the 28-day study period. Based on the agreements emanating from the special protocol assessment to assess blood pressure effects, the data from this single study supported approval of angiotensin II by the Food and Drug Administration for marketing in the USA.

Dysregulated activities of proline-specific enzymes in septic shock patients (sepsis-2)

“…In 2 patients multiple sites were identified (pneumonia/central line sepsis). The median (IQR) APACHE II score of 25 (20)(21)(22)(23)(24)(25)(26)(27)(28)(29), a duration of vasopressor treatment of 3.0 (1.5-8.5) days and the necessity to restart this treatment in 6 out of the 40 patients illustrate the severity of septic shock encountered in these patients. Additionally, 13 patients had died at day 90.…”

“…We report that PRCP activity is increased in the septic shock patient group on day 1. As PRCP is an angiotensin II degrading enzyme and angiotensin II is recently approved as therapy for septic shock [27,28], PRCP has the potential to become a promising predictive biomarker for response to angiotensin II. Angiotensin II treatment probably will not have the desired effect in patients with high PRCP activity.…”

“…PRCP is involved in the regulation of blood pressure and hypotension is common in sepsis and septic shock, moreover, angiotensin II is recently approved as therapy for distributive shock. Therefore, a possible role for PRCP in the pathogenesis of sepsis and septic shock is conceivable [4,27,28].…”

Terlipressin or norepinephrine in septic shock: do we have the answer?

“…Recently the United States Food and Drug Administration approved angiotensin II for the treatment of septic shock (5). There has been discussion of the FDA rationale for approving angiotensin II using and approving a novel primary endpoint of MAP elevation at three hours (21).…”

Physiologic Response to Angiotensin II Treatment for Coronavirus Disease 2019–Induced Vasodilatory Shock: A Retrospective Matched Cohort Study

“…Angiotensin-II is an U.S. Food and Drug Administration-approved treatment for distributive shock that reduces exogenous catecholamine requirements ( 8 , 9 ). In contrast to norepinephrine, angiotensin-II enhances T-lymphocyte and natural killer cell proliferation and function ( 10 , 11 ).…”