Angiotensin II: New Hope for Treating Septic Shock?

Greg Martin, MD


October 27, 2017

Angiotensin II for the Treatment of Vasodilatory Shock

Khanna A, English SW, Wang XS, et al; ATHOS-3 Investigators
N Engl J Med. 2017; 377:419-430


Septic shock occurs in the United States in approximately 200,000 people each year and leads to approximately 50,000 deaths,[1] and sepsis overall leads to approximately 1 in every 2-3 hospital deaths.[2] For patients with shock, fluid therapy is partially effective, but the cornerstone of pharmacologic therapy is use of vasopressors to mitigate the vasodilatory state.

The most common vasopressors are catecholaminergic drugs, such as norepinephrine, epinephrine, phenylephrine, and dopamine. More recently, vasopressin has become available for patients with septic shock and recommended as a second-line agent for shock refractory to norepinephrine.[3,4]

Study Summary

The authors of this study sought to determine the effectiveness of angiotensin II for blood pressure support in septic shock. They conducted a prospective, randomized clinical trial of 321 patients, comparing angiotensin II with placebo for the primary end point of a rise in mean arterial pressure of at least 10 mm Hg or to at least 75 mm Hg within 3 hours.

More patients in the angiotensin II group than the placebo group reached the primary endpoint (114 of 163 patients [69.9%] vs 37 of 158 patients [23.4 %], respectively; P < .001). The cardiovascular Sequential Organ Failure Assessment score decreased more in the angiotensin II group at 48 hours than in the placebo group (−1.75 vs −1.28 ; P = .01). Serious adverse events and adverse events leading to drug discontinuation were modestly fewer (but not statistically significantly less) in the patients in the angiotensin II group. Death by day 28 was similar between groups (46% vs 54 %; P = .12).

The authors concluded that angiotensin II effectively increases blood pressure in patients with septic shock who did not respond to high doses of conventional vasopressors.


This is an exciting and straightforward clinical trial of a new pharmacologic agent to increase blood pressure in vasodilatory shock. The study has limitations, however.

First, it was not sufficiently large to characterize all of the potential adverse effects or demonstrate an effect on mortality. However, the adverse event rates and mortality rates favored angiotensin II over placebo, suggesting a favorable risk/benefit assessment. Similarly, the study did not follow patients long-term to determine whether the drug may have adverse (or beneficial) effects on chronic organ dysfunction, recovery from critical illness, or long-term survival. And finally, as the authors pointed out, the active drug was more likely than placebo to result in a dose reduction in the conventional vasopressors being used for the patient, which would effectively unmask the providers as to whether the patient was receiving angiotensin II.

With these caveats, the results are awaiting US Food and Drug Administration consideration for approval of the drug for routine clinical use in the United States. This would add to the armamentarium for patients with shock, which includes conventional catecholamine-based vasopressors and inotropes, and vasopressin.

How these will fit into practice guidelines and be coordinated in clinical practice remains to be seen. In addition, more studies with angiotensin II may be useful to understand its effect on lung edema, for example, given the known role of angiotensin in salt and water homeostasis.



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