Synthetic Human Angiotensin II for the Treatment of Vasodilatory Shock Interview with:

Ashish Khanna, MD, FCCP Assistant Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine Staff Intensivist Center for Critical Care and Department of Outcomes Research Cleveland Clinic, Cleveland

Dr. Khanna

Ashish Khanna, MD, FCCP
Assistant Professor of Anesthesiology, Cleveland Clinic Lerner College of Medicine
Staff Intensivist
Center for Critical Care and Department of Outcomes Research
Cleveland Clinic, Cleveland How did you become interested in this topic?

Response: Anesthesia forms the basis of my training but I also completed a fellowship in critical care and, at the present time, I do more work in critical care than anesthesia. About 75% of my time is spent in the Cleveland Clinic critical care units, including the Medical and surgical ICUs (Intensive Care Units). What is the background for this study?

Response: First, it is important to note we are talking about the angiotensin II molecule itself, NOT the commonly used class of drugs called ARBs, which are angiotensin receptor blockers. ARBs reduce hypertension by blocking the effects of angiotensin. Angiotensin is a peptide formed in the liver but cleaved by the kidney enzyme renin and is thus part of the renin-angiotensin system. The primary effect of angiotensin II is to raise blood pressure by causing vasoconstriction.

The angiotensin II molecule was first synthesized in the 1950s, at the Cleveland Clinic by Dr. Irvine Page. LJPC-501 is La Jolla Pharmaceutical’s proprietary formulation of synthetic human angiotensin II. The ATHOS-3 study reported this week in the NEJM, was a multicenter, randomized, doubleblind, placebo-controlled, Phase 3 clinical study of LJPC-501 in patients with catecholamine resistant hypotension (CRH), a severe form of vasodilatory shock, most often due to sepsis.

La Jolla had originally performed a pilot study of 20 patients with high output shock. The ATHOS-3 study was conducted at the Cleveland Clinic under a special assessment program with the FDA.

The most frequent drugs used to support blood pressure (reverse hypotension) in patients with shock are vasopressin (ADH, Pitressin), norepinephrine (Levarterenol, Levophed) and dopamine. These drugs eventually reach high doses where therapeutic effect are not seen and can instead they may instead lead to side effects from excessive catecholamine release including but not limited to stress induced cardiomyopathy. The rationale for the study is that the by adding angiotensin II, we can hopefully decrease the use of vasopressin, norepinephrine and dopamine and thereby decrease the risk of adverse effects. We expect that hypotension will be treated with a cocktail of lower doses of medications including angiotensin II, similar to the use of multiple medications to manage hypertension. What types of patients were included in this study?

Response: We targeted patients with high cardiac output shock, most commonly due to sepsis but also due to other causes such as necrotizing pancreatitis or anaphylaxis. What should providers and patients take away from this report?
Response: Angiotensin LJPC-501 achieved the primary endpoint of increasing blood pressure in these patients with shock. It also achieved its secondary endpoint of cardiovascular improvement. At 48 hours, “improvement (indicated by lower scores) in the cardiovascular SOFA score* was significantly greater in the angiotensin II group than in the placebo group (−1.75 vs. −1.28, P=0.01)”.

*Sequential Organ Failure Assessment (SOFA) Score predicts ICU mortality based on lab results and clinical data.

Our study was not powered to measure mortality differences (which would require 1000+ patients). The study did show a trend toward improvement in mortality in the angiotensin arm, but was not statistically significant. It should be noted that none of the current medications for hypotension in shock demonstrate a mortality difference.

This work empowers providers with an important new tool in their armamentarium or the vasopressor toolbox. It makes complete sense physiologically to use all three arms of the blood pressure regulatory systems (i.e. catecholamine, vasopressin and now renin-angiotensin) to help fight resistant hypotension in the ICU. What recommendations do you have for future research as a result of this study?

Response: The next step has to be FDA approval for LJPC-501 so that the drug can be used in a wider context. There are many other ancillary ideas, including perhaps a head to head comparison with norepinephrine or the other vaso-supportive drugs, as well as a larger study with mortality as an endpoint. These studies will be time and resource intensive. Thank you for your contribution to the community.


Angiotensin II for the Treatment of Vasodilatory Shock
Ashish Khanna, M.D., Shane W. English, M.D., Xueyuan S. Wang, M.D., Kealy Ham, M.D., James Tumlin, M.D., Harold Szerlip, M.D., Laurence W. Busse, M.D., Laith Altaweel, M.D.,
Timothy E. Albertson, M.D., M.P.H., Ph.D., Caleb Mackey, M.D., Michael T. McCurdy, M.D., David W. Boldt, M.D., Stefan Chock, M.D., Paul J. Young, M.B., Ch.B., Ph.D., Kenneth Krell, M.D.,
Richard G. Wunderink, M.D., Marlies Ostermann, M.D., Ph.D., Raghavan Murugan, M.D., Michelle N. Gong, M.D., Rakshit Panwar, M.D., Johanna Hästbacka, M.D., Ph.D., Raphael Favory, M.D., Ph.D., Balasubramanian Venkatesh, M.D., B. Taylor Thompson, M.D., Rinaldo Bellomo, M.D., Jeffrey Jensen, B.S., Stew Kroll, M.A., Lakhmir S. Chawla, M.D., George F. Tidmarsh, M.D., Ph.D.,
and Adam M. Deane, M.D., for the ATHOS-3 Investigators*
This article was published on May 21, 2017, at
DOI: 10.1056/NEJMoa1704154

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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Last Updated on May 22, 2017 by Marie Benz MD FAAD