Happy New Year!

In this episode, I’ll discuss angiotensin II for the treatment of vasodilatory shock.

The FDA recently approved synthetic human angiotensin II for use under the trade name Giapreza.

After catecholamines and vasopressin, angiotensin II is now the 3rd class of agents approved for treating vasodilatory shock.

Angiotensin II binds to its specific receptors and exerts its effects on the brain, kidney, adrenal, vascular wall, and the heart. Angiotensin II raises blood pressure by causing vasoconstriction and increased aldosterone release.

The starting dose is 20 nanograms/kg/min. Titration occurs in increments of up to 15 ng/kg/min every 5 minutes. The maximum dose of angiotensin II during the first 3 hours of treatment is 80 ng/kg/min. The maximum dose past 3 hours should not exceed 40 ng/kg/min.

The plasma half-life of IV administered angiotensin II is less than 1 minute. Angiotensin II is metabolized by enzymes found in plasma, red blood cells, intestines, kidney, liver, and lungs.

The only suspected interactions with angiotensin II are with other medications that act on the renin-angiotensin system. ACE inhibitors will inhibit the metabolism of angiotensin II, likely prolonging or increasing the vasopressor effects. Angiotensin receptor blockers will likely decrease the effects of angiotensin II.

The most common adverse effects of angiotensin II are thromboembolic events, thrombocytopenia, tachycardia, fungal infection, delirium, acidosis, hyperglycemia, and peripheral ischemia.

There are no absolute contraindications to the use of angiotensin II. Because of the risk of venous thromboembolism, angiotensin II carries a warning that it should be used in conjunction with VTE prophylaxis.

The pivotal trial for the approval of angiotensin II was the ATHOS-3 trial published in NEJM May 2017. ATHOS-3 was a double-blind study in which 321 adults with septic or other distributive shock who remained hypotensive despite fluid and vasopressor therapy were randomized 1:1 to angiotensin II or placebo.

To be included in the study patients had to already be receiving at least 0.2 mcg/kg/min of norepinephrine or equivalent for at least 6 hours but no longer than 48 hours. 91% of the patients in ATHOS-3 had septic shock as their reason for hypotension. The primary endpoint was a response with respect to mean arterial pressure at hour 3 after the start of infusion. Response was defined as an increase from baseline MAP of at least 10 mmHg or an increase to at least 75 mmHg, without an increase in the dose of background vasopressors.

The primary endpoint was met in 70% of the angiotensin II group compared with 23% of the placebo group. In the angiotensin II group, the median time to reach the target MAP endpoint was 5 minutes. The median dose of angiotensin II at 30 minutes was 10 ng/kg/min. 98.2% of the responders required less than or equal to 80 ng/kg/min.

While the ATHOS-3 trial was sufficient to achieve FDA approval for angiotensin II, it answers few clinically relevant questions.

Is there a mortality or morbidity benefit to angiotensin II?

Is there a way to predict which patients will be responders to angiotensin II?

At what level of catecholamine dose is it time to add angiotensin II to vasopressor therapy?

What is the ideal combination of the 3 separate classes of vasopressors?

Unfortunately, these questions are not likely to be answered anytime soon. According to clinicaltrials.gov, there are no current studies using angiotensin II and clinically meaningful endpoints.

The high rate of venous thromboembolism in the angiotensin II group is very concerning and deserves more study. Was this difference due to chance or to some property of the drug? Were the patients who developed VTE in the ATHOS-3 study not receiving VTE prophylaxis? Until these questions are explored in future studies it is simply wishful thinking to assume that using VTE prophylaxis with angiotensin II will do anything to lower the risk of VTE.

With no known clinically meaningful benefit, and a potential increased risk of VTE, it will likely be very challenging to convince a P&T committee to add angiotensin II to the formulary.

Click here to access my free download area which contains the 7 questions I use to lead a topic discussion on vasopressors for my ICU students and residents.

If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.

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