Share this article on:


Szerlip, Harold; Bihorac, Azra; Chang, Steven; Chung, Kevin; Hästbacka, Johanna; Murugan, Raghavan; Favory, Raphael; Tumlin, James; Venkatesh, Balasubramanian; Chawla, Lakhmir; Tidmarsh, George

doi: 10.1097/
Star Research Presentation: Sepsis and Shock

1Baylor University Medical Center, Dallas, TX, 2University of Florida School of Medicine, Gainesville, FL, 3David Geffen School of Medicine at UCLA, Los Angeles, CA, 4Brooke Army Medical Center, Fort Sam Houston, TX, 5University of Helsinki and Helsinki University Hospital, Helsinki, Finland, 6University of Pittsburgh Medical Center, Pittsburgh, PA, 7University Hospital of Lille, Faculty of Medicine, Lille, France, 8University of Tennessee College of Medicine, Chattanooga, TN, 9Princess Alexandra Hospital, Brisbane, QLD, Australia, 10La Jolla Pharmaceutical Company, San Diego, CA

Learning Objectives: ATHOS-3 was a randomized, placebo-controlled, blinded study of patients with severe vasodilatory shock. In ATHOS-3, patients with persistent vasodilatory shock receiving > 0.2 μg/kg/min of norepinephrine or the equivalent were randomized to addition of intravenous angiotensin II (Ang II) (n = 163) or placebo (n = 158) with other vasopressors held constant for 3 hr, after which all vasopressors could be titrated through 48 hr to maintain mean arterial pressure (MAP). Ang II response was assessed as the dose required to achieve the target MAP. We assessed prespecified subgroups of ATHOS-3 with high severity of illness, as measured by elevated APACHE II score or baseline MAP < 65 mmHg, despite high dose vasopressors.

Methods: Severity of illness metrics (APACHE II > 30 [n = 123] and MAP < 65 mmHg [n = 102]) were prespecified and analyzed for 28-day all-cause mortality.

Results: A significantly higher proportion of patients receiving standard vasopressors plus Ang II vs vasopressors plus placebo, achieved the target increase of MAP, the primary study endpoint (69.9% vs 23.4% with placebo, P < .001); Ang II recipients also experienced more catecholamine sparing.1 We also observed a trend toward improved survival at day 28. Among all study patients, 28-day all-cause mortality was 46.1% in the Ang II group and 53.9% in the placebo group (HR=0.78; 95% CI = 0.57–1.07; P = .12). Greater mortality was seen in the placebo group than the Ang II group in patients with more severe disease at baseline: 28-day mortality, comparing the Ang II and placebo groups respectively, was 51.8% (n = 58) and 70.8% (n = 65) (HR 0.62; 95% CI = 0.39- 0.98; P = .037) in patients with APACHE II scores > 30 and 54.2% (n = 52) and 70.4% (n = 50), respectively, in patients with MAP < 65 mmHg (HR=0.66; 95% CI 0.40–1.09; P = .10).

Conclusions: Severely ill patients with severe vasodilatory shock (APACHE II scores > 30) who received Ang II + standard vasopressors had significantly improved survival at day 28 compared with patients who received standard vasopressors alone. A similar trend was seen for patients with baseline MAP < 65 mmHg. These findings suggest that activating the renin angiotensin aldosterone system (RAAS) with Ang II may address a significant unmet need in this critically ill patient population. 1 N Engl J Med 2017; doi:10.1056/NEJMoa1704154.

Copyright © by 2018 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.