Episode 91- Which patients respond best to Angiotensin II?

Hello and welcome to Episode 91 of ER-Rx- a podcast tailored to your clinical needs. I’m your host, Adis Keric. This week, I wanted to do an “Episode Revisit” about the use of Angiotensin II (ATII) or Giapreza. I first talked about ATII back in Episodes 26 and 27- going over the ATHOS-3 trial, my own personal experiences with using it, and then talked a bit about some controversial aspects like thrombosis, infection rates, and its effects on patients with COVID.

Since ATHOS-3 came out in 2017 there just hasn’t been much else published about ATII, and there are no professional guidelines that discuss how and when to use it- with most sites just coming up with their own protocols, typically using it as a third- or fourth-line vasopressor in patients with refractory shock. Since we don’t have much to go off of, I wanted to share what I found with you guys this week to hopefully help us all in our practices.

As a little background, ATII is an endogenous peptide and a component of the renin-angiotensin-aldosterone (RAS) system. Renin is released when our kidneys sense hypotension, and it then cleaves angiotensinogen into angiotensin I. Angiotensin I is then converted to Angiotensin II by angiotensin-converting-enzyme (ACE)—this sounds familiar because ACE-Inhibitors are used to decrease blood pressure. Once ATII is released, it binds to ATI and AT2 receptors, and when it binds to the AT1 receptor this causes vasoconstriction and increases blood pressure.

In ATHOS-3 and other small trials, response to ATII was evidenced by an increase in the MAP by about 10 mmHg and the ability to wean off of other background vasopressors—which happens in about 70 % of all patients who get ATII. The bummer is that it didn’t improve mortality rates; it didn’t even improve SOFA scores.

So if all ATII does is fix our numbers and clear up our MAR- is it worth giving it to anyone? Are there subgroups of patients who could benefit more?

In a review article from last year, the authors point out that ATII could be an attractive option in patients who develop vasoplegic shock after cardiopulmonary bypass (CPB)- which can occur in up to 20% of these patients. In a small subgroup analysis of the ATHOS-3 trial, which included 16 patients who underwent bypass, 8/9 patients who got randomized to ATII achieved the primary endpoint of MAP increase, whereas none of the other 7 patients who got placebo did. And although a tiny sample size, it still was a statistically significant difference.

They also mention that it could specifically be useful in patients with AKI. In another post-hoc analysis of ATHOS-3, patients with AKI had significantly higher survival rates if they got randomized to ATII versus placebo (53% vs 30%, P = 0.012). Patients who received ATII were also significantly more likely to be able to come off renal replacement therapy by day 7 compared to the placebo group (38% vs 15%, P = 0.007).

There was also another super interesting and recently-published, multi-center review article looking at real-world use of ATII. They, like us, wanted to try to figure out which patients respond to ATII by comparing responders to non-responders.

At the end, this review included 270 patients. Those who responded had similar baseline characteristics to those who didn’t. To get an idea of this patient population so that you can extrapolate it to your site, half of the patients had sepsis, 40% were admitted after surgical procedures and half of those were cardiovascular surgery patients. Their mean APACHE II scores were 30 (about the same as in ATHOS-3) and most had an average baseline lactate of 7.5. ATII was used mostly as the third or fourth-line agent, started a median of 11 hours after the first vasopressor.

First, just like in ATHOS-3 and my own personal experiences, about 70% of patients responded to ATII, with an average MAP increase of 10 mmHg. Here’s where things got interesting: Patients already on vasopressin were six times more likely to respond once they got started on ATII. We still don’t know why this is, but the authors think that the RAS and vasopressinergic systems act together to regulate fluid and blood pressure, or potentially that V1 receptors enhance the pressor effects of ATII. Either way, this is a really cool finding that we should keep in mind. Also, they found that patients with lower lactate levels (6.5 vs 9.5, P < 0.001) were significantly more likely to respond to ATII. Those two findings are important because response is linked to mortality. Patients who responded had significantly higher 30-day survival rates (41% vs 25%, P=0.001).

In another multi-center review of ATII use in 162 patients, they found that patients on less than 0.2-0.3 mcg/kg/min of NE equivalents prior to starting ATII had significantly greater reductions of background vasopressors compared to patients receiving higher background doses. Also, they found that patients on 3 vasopressors. So maybe it’s a good idea to start ATII earlier in the course of therapy, before any treatment becomes essentially futile.

To wrap up; we don’t have much guidance on how to use ATII or who to give it to. To be clear, just getting ATII doesn’t increase survival rates—but if your patient has a hemodynamic response to it—then they have a higher chance of survival. So until we get more guidance, it seems best to use it in patients that have a higher chance of responding to it.

So who are these patients? For now, this includes patients with vasoplegia after cardiopulmonary bypass, those with AKI or those on renal replacement therapy, or those with a lower baseline lactate level (< ~6-6.5). And given what we know now, it’s probably a good idea to make sure your patient is on vasopressin before ATII and to start ATII earlier. I’d think that starting it as a third-line agent, after norepi and vasopressin makes the most sense, and don’t wait until your patient is already on high doses of norepinephrine equivalents. For example, if a patient is on 0.1 mcg/kg/min of norepi and a continuous infusion of vasopressin, they are already on 0.2 mcg/kg/min of norepinephrine equivalents—and that may be an ideal time to start ATII. None of this waiting until the patient is on 1 of norepi, continuous vasopressin, and an epinephrine infusion for several hours because by then, it could be too late.

The last point I want to touch on is; Which vasopressor to come off of first if your patient is started on ATII. Some sites will turn off the vasopressin, others will wean down the NE- either way you do it, it doesn’t lead to any strong mortality benefits, but we do know from some small retrospective trials that stopping vasopressin first leads to more hypotension. Does what we know now about ATII make me rethink this? I think so. If patients are on NE, VP, and ATII, knowing that patients on VP had better responses to ATII—I think I’d try weaning the NE off first and continuing to run VP with ATII.

As always, thank you so much for your time, and thank you for wanting to learn more about pharmacotherapy. If you have any comments or anything you’d like to add to this episode, please give me a shout out on the @errxpodcast Instagram page, or reach out to me personally on errxpodcast.com- I’d love to respond to all comments and criticisms.

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