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Personalization Of Vasopressor Therapy In The Treatment Of Vasodilatory Shock
11 Plays6 years ago
In this episode of Critical Matters, listen to the recording of Sound Critical Care’s webinar, Personalized Selection of Vasopressors in the Treatment of Shock. Our guest for this episode is Dr. Lakhmir Chawla, Chief Medical Officer of La Jolla Pharmaceutical in San Diego, California.
During this webinar, we discuss lessons learned from the clinical use of the new vasopressor Angiotensin II, as well as personalization of vasopressor therapy in the treatment of vasodilatory shock.
Watch the video recording: https://bit.ly/2jZ1z5h
Recommended
Transcript
Introduction to Critical Matters Podcast
00:00:06
Speaker
Welcome to Critical Matters, a sound critical care podcast covering a broad range of topics related to the practice of intensive care medicine.
00:00:14
Speaker
Sound Critical Care provides comprehensive critical care programs to hospitals across the country.
00:00:20
Speaker
To learn more about our programs and career opportunities, visit www.soundphysicians.com.
Novel Therapy for Vasodilatory Shock
00:00:27
Speaker
And now your host, Dr. Sergio Zanotti.
00:00:32
Speaker
Welcome to our series of clinical webinars.
00:00:36
Speaker
from Sound Critical Care.
00:00:38
Speaker
We are very happy to have and honored to have a friend of Sound Critical Care, Dr. Lakmir Chawla, to talk about a novel therapy for vasodilatory shock and to hear about some new data that might lead the path for personalized treatments for patients with shock with angiotensin II and other vasopressors.
00:00:59
Speaker
So we are going to go ahead and get started.
Technical Issues and Audience Engagement
00:01:02
Speaker
We are having some technical difficulties,
00:01:04
Speaker
So we're going to share a link with the audience.
00:01:07
Speaker
We please ask that you watch the video, watch the link, and we will have Dr. Chawla and myself back on the webinar at the top of the hour to answer any questions that you may have, and you can enter those through the chat panel.
00:01:23
Speaker
Okay, I'd like to welcome everyone to this talk on personalized selection of vasopressors and the treatment of shock.
00:01:30
Speaker
Sergio, I very much appreciate the invitation to give this WebEx, and I hope to take you through some interesting data.
00:01:39
Speaker
Much of this is currently unpublished, and give you a sense of where we think things might be headed with utilizing
00:01:49
Speaker
biomarkers to help decide which vasopressor might be the most appropriate for patient vasodilatory shock.
Disclosure of Dr. Chawla's Role
00:01:57
Speaker
Importantly, there are some very important key disclosures that you should keep in mind when listening to this talk.
00:02:04
Speaker
The first is that I'm currently the chief medical officer of LaHoy Pharmaceutical Company, which is the company that makes the vasopressor angiotensin II.
00:02:14
Speaker
And I think perhaps the most important conflict is that
00:02:18
Speaker
I am the most conflicted human on planet Earth for Angiotensin II.
00:02:21
Speaker
I've been working on this product and this peptide for about a decade.
00:02:28
Speaker
And so whenever you have a scientific bias, that becomes something that you need to keep in mind
00:02:35
Speaker
whenever someone who has scientific bias is talking to you.
00:02:39
Speaker
So I'm sure you'll bear that in mind when looking and listening to these data.
Pilot Trial on Angiotensin II
00:02:45
Speaker
Nonetheless, I endeavor to give you a very scientific discussion and talk.
00:02:51
Speaker
So, this really starts about seven years ago or so, and we conducted a pilot trial, which was the first randomized controlled blinded trial of angiotensin II in the treatment of shock.
00:03:07
Speaker
And really the goal of this trial, which I did at George Washington University Hospital in Washington, D.C.,
00:03:13
Speaker
was to really understand the dose.
00:03:14
Speaker
If you look back in the previous literature, angiotensin II in the bovine form was available from about 1961 to around 1995 in the US.
00:03:25
Speaker
The drug was utilized then, it was safe, but the way they dosed the drug was incredibly inconsistent, and we really didn't have a good sense of what the appropriate dose was.
00:03:35
Speaker
And so the goal of this trial was safety, can we give the drug safely, and what dose should we give it in?
00:03:43
Speaker
And I'm not going to take you through the pilot trial.
00:03:45
Speaker
I think many of you listening to this have already seen this or at least read this study.
00:03:49
Speaker
The most, I think, important thing that happened during the conduct of this trial was that we came to recognize that there were some patients that were exquisitely sensitive to angiotensin II.
00:04:02
Speaker
such that while on high-dose catecholamines, specifically norepinephrine and vasopressin, when angiotensin-2 was initiated, the patients promptly became hypertensive.
00:04:14
Speaker
All the other vasopressors were completely weaned off.
00:04:17
Speaker
And on physiologic dose replacement, the patients remained hypertensive.
00:04:23
Speaker
And as a consequence of that, and I didn't really anticipate this in my protocol,
00:04:28
Speaker
We reported it as an adverse event.
00:04:30
Speaker
The infusions were stopped prior to the full amount of time that had been allotted.
00:04:36
Speaker
And when the angiotensin II was removed, and it has a very short half-life, angiotensin II, around 30 seconds to a minute, the requirement for all those vasopressors immediately came back.
00:04:48
Speaker
And, you know, it was really extraordinarily striking.
00:04:52
Speaker
You know, you don't see this type of response in clinical medicine that frequently.
00:04:57
Speaker
You know, these are the kinds of really dramatic responses you see when you give D50 to a patient who's profoundly hypoglycemic or giving cortisol to a patient who's profoundly Addisonian or giving Narcan to an overly narcotized patient.
00:05:10
Speaker
You know, it was extremely dramatic.
00:05:13
Speaker
And
00:05:14
Speaker
Initially, I had thought this was because these patients had been exposed prior to their critical illness with ACE inhibitors.
Endothelial Injury and ACE Dysfunction
00:05:24
Speaker
And that ended up being wrong.
00:05:25
Speaker
They hadn't been exposed to ACE inhibitors, and we were searching to understand why
00:05:30
Speaker
a patient who is critically ill may have an angiotensin II deficiency or insufficiency, we finally kind of realized that angiotensin-converting enzyme is an endothelioecto enzyme.
00:05:47
Speaker
And so what that basically means is that
00:05:50
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ACE doesn't do most of its work as a free-floating enzyme, although you can measure ACE in the blood.
00:05:57
Speaker
The vast, vast majority of angiotensin-converting enzyme capacity exists on the endothelium.
00:06:06
Speaker
And to a very large degree, it exists on the pulmonary endothelium.
00:06:11
Speaker
And what we came to recognize is that patients who get substantial endothelial injury, which is common in shock, I don't think people are confused about this notion of endothelium being involved in shock, the angiose-converting enzyme sloughs off and loses its ability.
00:06:31
Speaker
And this has been demonstrated previously quite elegantly.
00:06:34
Speaker
This is a very beautiful trial done by Orphanos and colleagues that was published in Circulation in 2000.
00:06:39
Speaker
And what they did is they looked at patients who had very severe ARDS, where at the time it was acute lung injury, and they took an ACE substrate.
00:06:49
Speaker
So this is a molecule that is metabolized by anadrogenase-converting enzyme.
00:06:55
Speaker
And they used this to assess ACE capacity in patients with acute lung injury.
00:07:00
Speaker
And what they found is using the old Murray Lung Injury score, which I actually prefer over the Berlin criteria, but my opinion about that's neither here nor there.
00:07:11
Speaker
And what you can see is quite beautifully that as your lung injury score goes up, your ability to convert angiotensin 1 to angiotensin 2 is diminished.
00:07:23
Speaker
The ACE capacity is diminished by severe lung injury.
00:07:28
Speaker
And so...
00:07:29
Speaker
Even though we didn't really outline this, I think, effectively in the pilot trial, Jean-Louis Vincent was very kind enough to allow us to write a letter in response to our own paper wherein we describe what we think is happening.
00:07:43
Speaker
And this was published a few years back in 2016.
00:07:48
Speaker
Basically, the sequence of events is as follows.
00:07:51
Speaker
You have an inflammatory insult, whether it be from trauma, sepsis, a toxin, whatever.
00:07:58
Speaker
And if you develop significant endothelial injury from whatever the initiating cause is, this can lead to significant and sustained loss of ACE activity.
00:08:12
Speaker
And it's not exclusively seen in patients with ARDS.
00:08:15
Speaker
Patients who have endothelial injury very broadly can demonstrate this kind of pathophysiology.
00:08:20
Speaker
And when this happens, what we have proposed is that you develop an angiotensin 2 insufficiency.
00:08:27
Speaker
And this angiotensin insufficiency leads to catecholamine resistance and acute kidney injury.
00:08:34
Speaker
I think for people who have good recall of the way Agitensin II works in the kidney, this is quite obvious.
00:08:41
Speaker
The issue of the catacombin resistance, interestingly, is not well appreciated by many.
00:08:45
Speaker
And here's a good example of that.
00:08:47
Speaker
This is a patient, this is a paper published in The Lancet in 1993, who
00:08:52
Speaker
And what you see is a patient who took an overdose of enalapril, a very well-known ACE inhibitor.
00:08:59
Speaker
And what you see is that despite catecholamines, they cannot maintain their blood pressure until they rescue the patient with angiotensin II.
00:09:09
Speaker
And it's not uncommon, and there are now case reports that show that angiosensin-2 effectively rescues an ACE inhibitor overdose, which is not surprising, and antihypertensive overdoses.
00:09:19
Speaker
But effectively, when you lose ACE function, and in this case, it wasn't through endothelial injury, it was through an active overdose of a toxin, which an allopril in high dose is a toxin,
00:09:31
Speaker
you get catecholamine resistance.
00:09:33
Speaker
And so, you know, this began to sort of continue to make us think about ACE function as being this really critical aspect of what is happening in a group of patients in shock.
00:09:47
Speaker
So I think just to reacquaint people with the renin-angiotensin-aldosterone system, I think everyone who's listening to this has at least heard of it, if not know it very well.
00:10:00
Speaker
And we refer to this construct as the RAS disturbance hypothesis.
00:10:05
Speaker
And essentially, everyone is very familiar with the angiotensinogen renin to age one, ACE converting age one to age two, and then aldosterone.
00:10:13
Speaker
And this is
00:10:14
Speaker
pretty well codified.
00:10:16
Speaker
The RAS system has been well understood and we continue to improve our understanding of it as the years go by as being a critical part of the way the body regulates blood pressure.
00:10:29
Speaker
However, when you get severe shock and endothelial injury, you hit a bottleneck.
00:10:36
Speaker
You're on the highway, six lanes go to two.
00:10:40
Speaker
And when that happens,
00:10:42
Speaker
The things that come before the bottleneck, such as renin and angiotensin 1, increase.
00:10:51
Speaker
And this is how we inform some of the way that we are testing the hypothesis of RAS disturbances being a critical function of endothelial injury and shock and hypotension.
FDA Approval of Angiotensin II
00:11:06
Speaker
And so when we went out and set out to get angiotensin II approved for the FDA, we set out to do a randomized and completed a randomized control trial, wherein we successfully randomized 344 patients and demonstrated that angiotensin II can safely improve blood pressure in those patients who are on high-dose catecholamines and or vasopressin.
00:11:36
Speaker
And that's the indication for which angiotensin-2 has, and it is now approved in both the United States of America, and it was approved by the EMA, and so it will be available in the 28 countries in Europe in 2019 and 2020.
00:11:52
Speaker
So, the brief summary of the phase three registration trial was that it was a test of angiotensin-2 as a vasopressor.
00:12:00
Speaker
The primary efficacy endpoint was MAP.
00:12:03
Speaker
But we were very keen to assess catecholamine reduction in safety, which we showed, but the goal was always to try and find the group of patients in whom we would be able to derive a survival benefit because we know at the end of the day that while MAP matters, in order for us to make progress in the treatment of shock, it has to be more than MAP.
00:12:30
Speaker
Now, just to remind those of you who are not completely familiar with this protocol, recognizing that the reviewers would take a very jaundiced eye to anything short of very rigorous resuscitation criteria, we utilize the surviving sepsis guidelines to make sure that all patients enrolled in the trial achieved appropriate levels of resuscitation.
00:12:54
Speaker
This is not the full inclusion or exclusion criteria.
00:12:57
Speaker
But patients with non-vasodilatory shock were excluded.
00:13:00
Speaker
You had to have a minimum of 30 cc per kg of crystalloid and demonstrate adequate resuscitation by either an adequate cardiac index or a CVP of 8 and a CVO2 of greater than 70%.
00:13:14
Speaker
And so we were rigorous about these criteria.
00:13:18
Speaker
And believe me, this was not fun because there was many, many, many patients in whom the clinician said, hey, I got a very patient for your trial, Mink.
00:13:25
Speaker
And, oh, wait a minute, there are CVPs too.
00:13:28
Speaker
Oh, there are CVPs four.
00:13:30
Speaker
You know, and what have you.
00:13:31
Speaker
And they weren't appropriately resuscitated, and those patients did not make the trial.
00:13:35
Speaker
We were very particular about these criteria because if you want to test a vasopressor, you have to make sure these patients are appropriate volume resuscitated.
00:13:45
Speaker
So this is the Kaplan-Meier curve showing you the mortality survival of patients in the ATHOS-3 trial.
00:13:54
Speaker
And you can see a very nice trend line and early separation between the two groups, but this did not achieve statistical significance.
00:14:01
Speaker
Realize and recognize that this trial was not powered to show a survival benefit.
00:14:06
Speaker
It was powered to show a MAP benefit, a catecholamine sparing benefit, and a safety profile that was acceptable, all of which we achieved.
00:14:16
Speaker
Importantly, we set out to understand and determine
00:14:22
Speaker
if the ACE effect was operational and important in the trial.
00:14:28
Speaker
And the way we did this is we measured the angiotensin 1 and angiotensin 2 levels at baseline.
00:14:34
Speaker
And the rationale for this is that we wanted to assess the function of endothelial ACE.
00:14:40
Speaker
As I mentioned previously, because measuring capacity of ACE on an endothelium is not so simple as a blood test, we sought to use the precursor, angiotensin 1,
00:14:52
Speaker
and its product, angiotensin II.
00:14:54
Speaker
And we basically made, we surmised that this ratio would help us understand the level of ACE function.
00:15:04
Speaker
And this was a pre-specified analysis in our statistical analysis plan and recognizing, as I said, endothelial ACE is the way by which ANG1 is converted to ANG2.
00:15:13
Speaker
Now, this is not the only way that ANG1 becomes ANG2.
00:15:17
Speaker
There are some other mechanisms that do exist, but they don't appear to be very operational in shock.
00:15:24
Speaker
And that, perhaps, is something, Sergio, we can talk about at the end of the talk in the questions.
00:15:30
Speaker
Now, if you look at the patients, now the median value, the edge one, edge two ratio in the entire trial is 1.6.
00:15:37
Speaker
Recognize that the normal value is 0.5.
00:15:41
Speaker
So in shock, the edge one, edge two ratio is quite disordered.
00:15:46
Speaker
And if you are closer to the normal range, you do not see a survival benefit.
00:15:51
Speaker
However, if your ratio is elevated,
00:15:56
Speaker
We demonstrate a statistically significant survival benefit in a pre-specified analysis, which is a really big deal.
00:16:03
Speaker
And we were really pleased to show this result because this was not data dredging at the end.
00:16:09
Speaker
This was an a priori hypothesis.
00:16:13
Speaker
And we were able to show that if you use the ratio, you can, in fact, identify those patients who gain a survival benefit with angiotensin II.
Development of Diagnostic Tests
00:16:22
Speaker
which was a really nice thing and we were pleased to do that however there's a non-trivial problem with this which is this right so we've shown this to many many people and people are very excited by this they say this this makes sense i think this is a very logical um you you specified this before the trial was done however
00:16:47
Speaker
norepinephrine is very cheap.
00:16:49
Speaker
The hospital environment is incredibly austere.
00:16:54
Speaker
We really want to use angiotensin 2 when we know we get a survival benefit and not just a MAT benefit.
00:17:01
Speaker
And so when will you provide us the angiotensin 1, angiotensin 2 bedside test that drops into an ISTAT?
00:17:09
Speaker
I think it's the right request, but the answer is this is not going to happen anytime soon.
00:17:16
Speaker
And allow me to take a belief diversion into why this will not happen anytime soon.
00:17:23
Speaker
The reason this will not happen anytime soon is because if you have a companion diagnostic that drives care that is new, that test needs to be validated, developed, and then FDA approved.
00:17:37
Speaker
And that process is, aside from being expensive, takes a lot of time.
00:17:44
Speaker
because you have to develop these assays that are very robust
00:17:48
Speaker
You then have to make them robust that they have very low coefficient of variations.
00:17:52
Speaker
You then have to put it onto a platform.
00:17:54
Speaker
You have to validate that platform.
00:17:56
Speaker
You have to build the platform.
00:17:58
Speaker
And then you have to show in a new study that that exact companion diagnostic maps to the outcome that you said.
00:18:08
Speaker
And I think all of that is well worth doing, but it doesn't happen fast.
00:18:12
Speaker
And so we have sought to find...
00:18:17
Speaker
something that allows the clinician to arrive at this determination sooner because while this process continues, it takes years, many years in fact.
00:18:28
Speaker
So we were thinking hard about what a test would be that would do this, and we had considered renin for quite some time as a possibility.
Renin Measurement in ICU Survival
00:18:40
Speaker
And to be honest, I didn't initially look at renin because I was concerned that it may not be very stable.
00:18:50
Speaker
There is not a lot of literature on how renin functions in the blood of shock patients who are with or without acute kidney injury, whether the assay is very robust.
00:19:02
Speaker
And I was just profoundly delighted to see this paper published by
00:19:07
Speaker
Gleason and colleagues, which is based out of Jacques Couture's and Jean-Louis Vincent's shop in Brussels, Belgium.
00:19:14
Speaker
And what they showed, and I think it's probably hard to read on the slide, this entire abstract, but basically in a large heterogeneous ICU population, renin measurement was very
00:19:27
Speaker
It wasn't affected by diurnal variation.
00:19:29
Speaker
It wasn't affected by other drugs.
00:19:31
Speaker
There are some data that suggest that catecholamines can affect reading levels.
00:19:34
Speaker
They did not see this.
00:19:36
Speaker
And importantly, it's not affected by dialysis.
00:19:40
Speaker
And I think the thing that stunned me is that it outperformed lactate.
00:19:47
Speaker
I'm going to say this again because...
00:19:50
Speaker
This is not obvious.
00:19:52
Speaker
Renin outperformed lactate as a predictor of ICU survival.
00:19:59
Speaker
Which is really quite remarkable.
00:20:01
Speaker
And I think that gave me an enormous amount of confidence to say, you know what, I think renin may be something that helps us in assessing these patients.
00:20:12
Speaker
After all, renin is in the RAS system.
00:20:16
Speaker
It is the R in the RAS system.
00:20:17
Speaker
It is the renin-angiotensin-aldosterone system.
00:20:22
Speaker
And so I'll show you some of the data related to this.
00:20:26
Speaker
So the first thing we set out to do is, does the renin correlate with the ratio?
00:20:30
Speaker
So can it be used in place of the ratio?
00:20:33
Speaker
And the answer is yes.
00:20:35
Speaker
The p-value is highly statistically significant.
00:20:38
Speaker
And what you see is a very nice correlation between renin and the ang1-ang2 ratio.
00:20:43
Speaker
So that was a good first step to give us confidence that this might actually be a way in which to guide care.
00:20:51
Speaker
Now, if you look at the patient population, the patients who have a low renin, right?
00:20:56
Speaker
So these are patients who are normal.
00:20:58
Speaker
Their angiotensin-converting enzyme capacity is more normal.
00:21:02
Speaker
There is no survival benefit.
00:21:03
Speaker
What you can see is these two curves are superimposed on one another, and there is no survival benefit.
00:21:09
Speaker
However, if you don't have...
00:21:13
Speaker
good adjutantin-converting enzyme function, the renin is high, and when you look at these folks, what you see is a highly statistically significant survival benefit.
00:21:26
Speaker
The relative risk is 0.55.
00:21:29
Speaker
The difference here in survival is 50% versus around 70%, which is an absolute delta of 20%.
00:21:36
Speaker
That means in the high renin group, the number needed to treat to save one life is five.
00:21:44
Speaker
Single-digit number needed to treat is simply outstanding.
00:21:48
Speaker
And I want you to look at the early separation here.
00:21:52
Speaker
These high renin patients who get placebo die very quickly.
00:21:56
Speaker
By day seven, half are dead.
00:21:59
Speaker
by day seven, half are dead.
00:22:03
Speaker
Right?
00:22:04
Speaker
So this is a way in which we are able to show a difference between the two arms based on a readily available test that has high statistical significance.
00:22:16
Speaker
Of course, as always,
00:22:18
Speaker
The rubber meets the road in the multivariate analysis, and angiotensin II treatment holds up.
00:22:25
Speaker
It remains statistically significant when you adjust for the stratification variables and the variables that were imbalanced in the trial.
00:22:34
Speaker
with a hazard ratio of 0.62, which means it gives you a 38% survival benefit that is statistically significant.
00:22:41
Speaker
So this has allowed us to feel very confident that we can use renin as a way to help identify patients who gain a survival benefit in a vasodilatory shock.
00:22:56
Speaker
Now, I think the thing which really pleased me was that you also saw an enhanced safety profile.
00:23:03
Speaker
So in these patients who received angiotensin II in the high renin arms, this is the elevated renin group of patients, what you see is in addition to gaining a survival benefit, they have less adverse events,
00:23:16
Speaker
They have less high-grade adverse events, which is essentially serious adverse events.
00:23:21
Speaker
And the reason why this is important is recognize that when these folks in the placebo arm die, they no longer contribute serious adverse events.
00:23:32
Speaker
So these folks live for 28 days, and they give you all this extra time compared to these folks that are mostly dead to give you serious adverse events, and there's still fewer in this arm.
00:23:44
Speaker
That is not what you normally see.
00:23:46
Speaker
What you normally see is enhanced survival, survival bias, contributing more events because these folks are around in ICU, they're in the hospital, more stuff can happen to them.
00:23:55
Speaker
So not only do you...
00:23:59
Speaker
use renin to allow you to identify the patients who get a spherol benefit, it allows you to be safer.
00:24:05
Speaker
And that is something which you don't see very much, and we were very happy about this result in this finding.
00:24:12
Speaker
Now, I think there's an important question here, which is that, why does the renin go up?
00:24:18
Speaker
Could it be up for other reasons?
00:24:20
Speaker
I mean, are you missing something?
00:24:22
Speaker
Well,
00:24:23
Speaker
There are other things that make the renin go up.
00:24:26
Speaker
One of them is essential hypertension.
00:24:28
Speaker
The good news here is that everybody was in shock, so hypertension is really not a problem.
00:24:32
Speaker
Malignant hypertension can also raise your renin.
00:24:35
Speaker
Not an issue.
00:24:35
Speaker
These patients are profoundly hypotensive on high-dose vasopressors.
00:24:39
Speaker
Could they be bleeding?
00:24:40
Speaker
Bleeding does increase your renin, but active bleeding was an exclusion criteria in the trial.
00:24:47
Speaker
Cirrhosis can raise your renin, also excluded in the trial, liver failure.
00:24:52
Speaker
I think the most common thing people tend to see is renal vascular hypertension and, of course, exceedingly rare renin-producing tumor.
00:25:00
Speaker
So if you sort of look at this, this is the normal range of the assay, 0 to 50.
00:25:09
Speaker
This is what happens when you have renal artery stenosis.
00:25:13
Speaker
You get yourself up to around 150, maybe 200.
00:25:17
Speaker
This is the range at those three.
00:25:20
Speaker
The median value is 161, which is around three times the upper limit of the normal of the assay.
00:25:25
Speaker
It told you it was 0 to 50, so it was 150.
00:25:28
Speaker
The highest value is up as close to nearly 6,000.
00:25:30
Speaker
So the renins are not slightly elevated.
00:25:36
Speaker
They're unbelievably elevated.
00:25:39
Speaker
And these data match very closely to the range of renin shown in shock by the Gleason data.
00:25:46
Speaker
And so this is not just us and our data saying that the renins are high.
Evidence on ACE Inhibitors
00:25:50
Speaker
This is mapping and matching directly to other data published looking at this exact type of effect.
00:25:58
Speaker
So I think, you know, it's important to think about this
00:26:03
Speaker
Is ace dysfunction, does it behave in the way that we are imagining it that it should?
00:26:11
Speaker
So if there's a block in the road, antitensin-converting enzyme is not working, do these things actually back up?
00:26:18
Speaker
And so if I were a bench scientist, or if I had a lot of money and could do a lot of healthy volunteer studies, how would I test this?
00:26:25
Speaker
How would I go about trying to understand how to make this assessment?
00:26:31
Speaker
So the simplest way to do it is to give an ACE inhibitor.
00:26:34
Speaker
So an ACE inhibitor is an incredibly controlled way in which to assess the
00:26:41
Speaker
the effect of angiotensin-converting enzyme dysfunction because you induce it with the drug.
00:26:47
Speaker
And if you give an allopril, this should not surprise anyone, the blood pressure goes down.
00:26:53
Speaker
Well, not only that, the renin goes up.
00:26:58
Speaker
So you give an allopril, blood pressure goes down.
00:27:02
Speaker
Renin goes up.
00:27:03
Speaker
That makes sense.
00:27:04
Speaker
Okay.
00:27:05
Speaker
Well, if you look at this in a very deliberate fashion, this is a trial published in 1979 by a Japanese group in Kyoto.
00:27:15
Speaker
And they used Captopril, which back then was a squib molecule, squib 14-225.
00:27:23
Speaker
And what they did is they took healthy volunteers and they gave them Captopril.
00:27:27
Speaker
And what you can see over a two-hour period of time, which I think in my mind is quite dynamic,
00:27:33
Speaker
you see nearly a doubling of the renin in two hours.
00:27:40
Speaker
More importantly, you similarly see over 120 minutes, around two hours, a 260% increase, so a doubling plus of your adjutensin 1, which makes sense, right?
00:27:51
Speaker
So, adjutensin-converting enzyme is not working.
00:27:55
Speaker
It's pulled down by enalopril.
00:27:57
Speaker
There is a
00:28:00
Speaker
narrowing of the freeway, you're going from six lanes to two, and the renin and angiotensin one back up.
00:28:06
Speaker
This makes sense, and this has now been shown experimentally, both in preclinical models, which I haven't shown you, but now in healthy volunteers getting Captipro.
00:28:16
Speaker
I think the more important question is what happens to a patient in whom you've induced an ACE defect with enalapril or captopril when you give them angiotensin 2.
00:28:26
Speaker
And they actually did this in 1979.
00:28:29
Speaker
And what you see quite beautifully is when you give angiotensin 2 to someone who has had a deliberate
00:28:38
Speaker
embarrassment of adjutensin-converting enzyme function is there is biofeedback and the renin goes down.
00:28:47
Speaker
The engagement of the ATR1 receptor with adjutensin 2 causes an appropriate biofeedback response of renin reduction.
00:28:58
Speaker
And so we set out to sort of characterize this, and we published these data in 2018 in critical care.
00:29:07
Speaker
And essentially, what we're saying is this.
00:29:09
Speaker
You get endothelial injury, typically from septic shock.
00:29:13
Speaker
But as anyone who's listening to this WebEx knows, it can be from a variety of different things.
00:29:19
Speaker
And if that happens, you get less effective ATR1 receptor engagement because there's not enough angiotensin to around other things.
00:29:29
Speaker
This then causes an increase in renin.
00:29:32
Speaker
which causes the body to increase the production of angiotensin 1.
00:29:36
Speaker
Now, if you then bring angiotensin 2 exogenously into this environment, you engage the ATR1 receptor, this then sets off appropriate biofeedback.
00:29:48
Speaker
This is demonstrated in healthy volunteers who have deliberate ACE inhibition, ACE dysfunction initiated.
00:29:57
Speaker
This is also shown in preclinical models.
00:29:59
Speaker
the renin goes down, which should cause the angiotensin I levels to go down.
00:30:05
Speaker
So if the RAS disturbance hypothesis is operative in shock patients, what you ought to see
00:30:15
Speaker
is a reduction in renin and angiotensin 1 with the introduction of angiotensin 2 into that environment.
00:30:24
Speaker
And that is exactly what we see.
00:30:27
Speaker
So here are the patient's angiotensin 1 levels.
00:30:31
Speaker
In placebos in red, you can see it's quite flat.
00:30:34
Speaker
The change is around 8.5%.
00:30:35
Speaker
This is baseline.
00:30:38
Speaker
And now you have either drug or placebo.
00:30:40
Speaker
And then hour 3 later.
00:30:42
Speaker
And what you can see...
00:30:44
Speaker
is when you get angiotensin II, which is LJPC501, you have a 34% reduction in your angiotensin I levels, which is a pretty big reduction in a very short period of time.
00:30:57
Speaker
And the renin follows directly in suit, in lockstep, as anticipated,
00:31:04
Speaker
you'd expect to see if you have significant ACE dysfunction.
00:31:09
Speaker
In the placebo arm, you can see it's very flat.
00:31:12
Speaker
And here, with those folks who get angiotensin II, you get a marked reduction, a 50% reduction in just three hours.
00:31:21
Speaker
And obviously, both of these findings are highly statistically significant.
00:31:25
Speaker
And so remember that all these placebo patients, right, they're all well-resuscitated.
00:31:33
Speaker
Okay?
00:31:34
Speaker
They're all on catecholamines.
00:31:37
Speaker
And 70% of them are vasopressin.
00:31:39
Speaker
So this inability to decrease your renin and angiotensin 1, respectively, is not because they have a catecholamine, vasopressin, or crystalloid defect.
00:31:53
Speaker
This is about the difference between getting angiotensin 2 versus placebo.
00:31:58
Speaker
Now,
00:32:00
Speaker
My colleague and friend, Steve Chen, who works with me here at La Jolla Pharmaceutical, when we looked at these data, asked me, I think, a pretty profound question.
00:32:07
Speaker
He said, you know, Mink, the angiotensin 1 level is dropping so massively.
00:32:12
Speaker
It's really striking.
00:32:13
Speaker
He said, could some of the benefit that we're seeing be because the angiotensin 1 level goes down?
00:32:21
Speaker
Is angiotensin 1 bad for you?
00:32:25
Speaker
And that's a pretty good question.
00:32:26
Speaker
And, you know, it turns out that he was right.
00:32:29
Speaker
And I'll show you why.
00:32:30
Speaker
So, you know, if you think about the classical pathway of angiotensin metabolism, it goes from angiotensinogen to renin to ang1 to ACE to ang2.
00:32:39
Speaker
And we've already been through this once in this talk, and many of you know this already.
00:32:43
Speaker
But there's also...
00:32:44
Speaker
a non-classical pathway of angiotensin metabolism.
00:32:48
Speaker
And this pathway is in contradistinction to the classical pathway, which is vasoconstrictive.
00:32:58
Speaker
This pathway is the opposite.
00:33:01
Speaker
It's vasodilatory.
00:33:03
Speaker
And what happens is if there is ACE dysfunction, you then can have angiotensin 1 being metabolized to angiotensin 2 to 7,
00:33:13
Speaker
and 1 to 7.
00:33:15
Speaker
And if there's an ACE defect, this can then cascade, right?
00:33:20
Speaker
So, if you have an ACE defect either from an angiotensin-converting enzyme inhibitor or profound endothelial dysfunction, what we think is happening is that your renin goes up, your ANG1 goes up, and it can't go down this pathway.
ACE Dysfunction and Vasodilatory Pathways
00:33:36
Speaker
It gets shunted in 2 to 7 and 1 to 7.
00:33:40
Speaker
And we also know that bradykinin levels are elevated in shock, and that's important because bradykinin is also a profound vasodilator.
00:33:50
Speaker
And so...
00:33:51
Speaker
What we think is happening is that this non-classical pathway is becoming much more operational.
00:33:58
Speaker
Now, many of you have not heard of these other angiotensins, 2 to 7, 1 to 7, and whatnot.
00:34:02
Speaker
And I just want to show you some data to show you that these data are really well-sorted already.
00:34:07
Speaker
This has been worked out.
00:34:09
Speaker
These are data published in 1996, and these are patients who are being initiated on Captopril for hypertension.
00:34:16
Speaker
And what they find is that your angiotensin 1 to 7 levels
00:34:21
Speaker
are the key to gaining a hypotensive, a decrease in your high blood pressure.
00:34:28
Speaker
This is a graph showing you the diastolic blood pressure plotted against the plasma angiose 1 to 7 level.
00:34:34
Speaker
And what you can see is the more your angiose 1 to 7 level goes up, the more your blood pressure goes down.
00:34:41
Speaker
Anginism 1 to 7 is a highly effective vasodilator.
00:34:45
Speaker
It's such an effective vasodilator that it's being worked on by other drug companies as an antihypertensive.
00:34:52
Speaker
And, you know, I think this paper that recently came out, I think, really shows this beautifully.
00:34:57
Speaker
This is a group of animal studies where they take anginism 1 to 7 and they look at the GFR in patients, not especially on patients, but in animals.
00:35:11
Speaker
And what you see here is GFR is over here on the y-axis.
00:35:15
Speaker
And in the control arms, what you can see is when you give angiotensin 1 to 7, you have this small diminishment in GFR.
00:35:22
Speaker
But if you are hyperfiltering from induced diabetes, there's this big drop in GFR.
00:35:27
Speaker
But I think more importantly, and this may be more operational for the renal geeks who are listening to this,
00:35:33
Speaker
Look at the change in filtration fraction.
00:35:36
Speaker
This is the effect of the intraglomerular pressure assessment.
00:35:41
Speaker
Angiotensin 1 to 7 functions as the polar opposite of angiotensin 2.
00:35:48
Speaker
Angiotensin 2 increases filtration fraction.
00:35:51
Speaker
Angiotensin 1 to 7, which is one amino acid different, has the exact opposite effect.
00:35:57
Speaker
In essence, angiotensin 1 to 7 is the opposite of angiotensin 2.
00:36:03
Speaker
So when you have higher levels of angiotensin 1 to 7 due to ACE dysfunction, you not only get not enough angiotensin 2, you get the opposite of angiotensin 2, angiotensin 1 to 7, increasing significantly, which has
00:36:23
Speaker
important intrarenal GFR filtration fraction effects.
00:36:30
Speaker
Let me show you some longitudinal data to try and put this into some context.
00:36:35
Speaker
So this is a group of patients, this is from maternal hypertension, 1996.
00:36:39
Speaker
And what you see here are angiotensin I and angiotensin II levels in patients who are naive to captopril.
00:36:47
Speaker
So this is the initial dose of captopril baseline.
00:36:50
Speaker
They have not received their captopril yet.
00:36:51
Speaker
And what you can see
00:36:53
Speaker
is that the angiotensin 2 level is about 2x that the angiotensin 1 level, which is why the baseline ratio is around 0.5.
00:37:01
Speaker
So now, you get your capitol dose.
00:37:04
Speaker
You've received an ACE inhibitor.
00:37:06
Speaker
What happens to your angiotensin 2 level?
00:37:09
Speaker
It doesn't go down.
00:37:11
Speaker
But your angiotensin 1 level goes way up.
00:37:16
Speaker
Now, it's six months later.
00:37:17
Speaker
You've been on capitol three times a day.
00:37:20
Speaker
This is your pre-dose.
00:37:23
Speaker
And what you can see is that your pre-dose looks very similar to your post-dose back over here.
00:37:30
Speaker
Notice the angiotensin II level is not lower than the first day that they started.
00:37:36
Speaker
Now you get your catapryl dose and you look at your post-dose.
00:37:41
Speaker
The angiotensin II level has not gone down.
00:37:45
Speaker
But your angiotensin I level has gone way up.
00:37:47
Speaker
And this has been shown in many other studies.
00:37:51
Speaker
And this is something which I know you're going to find hard to believe, but go check the literature on your own if you don't believe me.
00:38:00
Speaker
ACE inhibitors don't cause dramatic drops in angiotensin II.
00:38:07
Speaker
ACE inhibitors do not cause dramatic drops in angiotensin II.
00:38:13
Speaker
What they do do is cause dramatic increases in angiotensin 1 and angiotensin 1 non-classical pathway angiotensins, which are vasodilatory and are the drivers of the hypotension effects of ACE inhibition.
00:38:36
Speaker
This is from the heart failure literature and the hypertension literature.
00:38:39
Speaker
I have not shown you any shock data yet when it comes to this.
00:38:44
Speaker
So basically, what we think is happening when you integrate the data from the heart failure literature and hypertension literature about ACE inhibition and the RAS disturbance hypothesis is this.
00:39:05
Speaker
You take these patients who have significant angiotensin-converting enzyme dysfunction,
00:39:12
Speaker
you give them angiotensin 2 back, and it initiates a process of biofeedback.
00:39:18
Speaker
Now, I've already shown you the renin goes down and the angiotensin 1 goes down.
00:39:24
Speaker
When that happens, you get less vasodilatory non-classical pathway angiotensins.
00:39:33
Speaker
You remove angiotensin.
00:39:36
Speaker
bad-acting vasodilators.
00:39:38
Speaker
These vasodilators, if you have heart failure, if you have hypertension, are glorious and wonderful.
00:39:43
Speaker
If you are in shock, not so bueno.
00:39:47
Speaker
Because these are ACE metabolites, it's likely, and this is now supposition, that this ACE availability likely increases, which also decreases bradykinin.
00:40:03
Speaker
Now, this is sort of a lot to take in, and this is sort of like too many boxes with too many colors.
00:40:09
Speaker
If you remember nothing else from this WebEx, this is the slide that you should recall.
00:40:17
Speaker
Basically, what I am saying is that when you have an angiotensin-converting enzyme defect, it causes an imbalance.
00:40:28
Speaker
And this imbalance favors vasodilation.
00:40:32
Speaker
with increases of angioma-1-7, bradykinin, and other non-classical angiotensins, which I refer to as angiotensin detritus.
00:40:44
Speaker
ACE impacts not just macro, but micro-hemodynamic alterations.
00:40:51
Speaker
And we believe that the
00:40:56
Speaker
introduction of angiotensin 2 doesn't just treat the ACE defect's impact on not enough angiotensin 2, but decreases the renin, the ang1, and all these other beta-xylators, thus treating both sides of this scale.
Serumina Test for Treatment Candidates
00:41:14
Speaker
Because essentially, you have a dual defect when you have angiotensin-converting enzyme dysfunction.
00:41:22
Speaker
Importantly...
00:41:26
Speaker
these patients can be identified with a cheap, readily available test that is available in every major medical center in the country, which is Serumina.
00:41:37
Speaker
Now, allow me to sort of take you back to some basic
00:41:44
Speaker
renal physiology.
00:41:45
Speaker
And for those of you who know this well, I apologize in advance because this is profoundly rudimentary to your physiology training in your first year of medical school.
00:41:55
Speaker
But, you know, we know that in a normal glomerulus, efferent tone is what manages the intraglomerular pressure, which generates ultrafiltrate, which becomes your urine output.
00:42:10
Speaker
In an inhibited and dysfunctional state,
00:42:14
Speaker
The efferent arterial is vasodilated.
00:42:18
Speaker
This decreases the intraglomerular pressure, which causes less ultrafiltrate.
00:42:28
Speaker
When you restore angiotensin to effect... And now, remember, this is not just...
00:42:35
Speaker
by giving angiotensin 2, it's by reducing angiotensin 1 to 7 as well, because the net effect is all of that.
00:42:43
Speaker
You restore intraglyneural pressure when you get efferent tone back, and this improves filtration and ultrafiltrate.
00:42:54
Speaker
And if this were true, what you'd expect to find in the ATHOS-3 trial is patients with acute kidney injury and shock
00:43:03
Speaker
The most severe ones are the ones who ought to benefit.
00:43:05
Speaker
And that's exactly what we show.
00:43:08
Speaker
This is data published in Critical Care Medicine 2018.
00:43:13
Speaker
I want you to look at this.
00:43:14
Speaker
The median renin level in the AKI patients is 352.
00:43:19
Speaker
The median for the overall population is 161.
00:43:20
Speaker
Right?
00:43:20
Speaker
So what this means...
00:43:27
Speaker
is patients with AKI have a more severe ACE disturbance, as you'd expect.
00:43:34
Speaker
High renin means low effective angiotensin II and low GFR.
00:43:39
Speaker
When you give angiotensin II to these patients, you see a really dramatic survival benefit.
00:43:46
Speaker
The p-value is highly statistically significant, 0.01.
00:43:51
Speaker
And what you see is a hazard ratio of around 0.5, which, by the way, is very similar to what I showed you in the hymenin group, because these two groups largely co-localize.
00:44:02
Speaker
But I think the most important thing is not just a survival benefit.
00:44:08
Speaker
And you can say, geez, mate, what's more important than survival?
00:44:11
Speaker
I will tell you as a nephrologist,
00:44:14
Speaker
getting off of dialysis is really important.
00:44:18
Speaker
And this is exactly what we show.
00:44:20
Speaker
Those patients who have AKI on renal replacement therapy, who get angiotensin II, recover from RRT much more rapidly in a highly statistically significant fashion.
00:44:34
Speaker
Now, you know...
00:44:37
Speaker
I recognize that bringing in a new drug is expensive.
00:44:43
Speaker
I want you to take an assessment of how much CRRT costs a patient on a given day, how much intermittent hemo costs a patient on a day, what CKD does for a patient to a health care system, for that individual person's risk moving forward.
00:44:57
Speaker
And if you don't ever get them fixed and they do manage to survive, they become an ESRD patient.
00:45:04
Speaker
angiotensin II, more rapid renal recovery.
00:45:07
Speaker
What are you doing for AKI now, aside from more dialysis?
00:45:13
Speaker
And we mechanistically link this.
00:45:15
Speaker
And just so you understand what I'm trying to say here, I want to just spend a moment differentiating two key concepts.
00:45:23
Speaker
So, Rinaldo Belomo has been particular, and he has said to me, Mink, listen, it's really important that we get our nomenclature down and specify the difference between a biotype and a clinical phenotype.
00:45:38
Speaker
So a biotype is your high renin or low renin state, or whether you're estrogen receptor positive for your breast cancer or HER2 positive for your breast cancer.
00:45:50
Speaker
That's a biotype.
00:45:51
Speaker
It's a biologic assessment of the subform of disease that you have.
00:45:55
Speaker
So we know now that high renin and low renin are biotypes of vasodilatory shock.
00:46:04
Speaker
Having ARDS or acute kidney injury requiring renal replacement therapy, that's your clinical phenotype.
00:46:10
Speaker
So if you look at this, not all, but about 75% of the patients who have AKI requiring renal replacement therapy are high renin.
00:46:22
Speaker
So if you can't get renin measured in your hospital center and you want to sort of say, well, how do I pick those patients?
00:46:30
Speaker
It's a patient with severe acute kidney injury.
00:46:34
Speaker
It's just that simple.
00:46:35
Speaker
Now, it's not perfect, but it's pretty good.
00:46:37
Speaker
75% to 85% of the time, you're going to be able to localize that high renin group just on that clinical phenotype.
00:46:47
Speaker
However, if you have renin available, which is a very inexpensive test, then you can make that determination much more rapidly and then precision guide the utilization of a vasopressure
00:47:04
Speaker
of a razor presser to improve an outcome.
00:47:07
Speaker
And I think that it's important to recognize that when you do this latent subclass analysis stuff and you're using clinical phenotypes, you need to be really careful because these things can be a little bit unstable.
00:47:20
Speaker
When you do a latent subclass analysis, or in our case, an analysis based on a singular biomarker, that is a little bit more reproducible because we know exactly what that marker is and we can measure a specific concentration.
00:47:34
Speaker
And high renin, I think for purposes of this localization of biotype, is three times the upper limit of normal.
00:47:42
Speaker
So, if you're labbed, the upper limit of normal is 40, it's 120.
00:47:46
Speaker
In our trial, the renin assay we used, the upper limit of normal was 50.
00:47:50
Speaker
And so, we used a median cutoff.
00:47:52
Speaker
So, 150 is very close to the medians.
00:47:54
Speaker
And we've done a sensitivity analysis looking at this.
00:47:57
Speaker
And it's not just the median happens to be so simplistic.
00:48:01
Speaker
It happens to be where you get the most...
00:48:03
Speaker
benefit lined up when you look at it through different cutoffs as well.
00:48:06
Speaker
I didn't show you those data in the interest of time, but I think it's important for you to know that.
Biological vs. Clinical Shock
00:48:12
Speaker
Most importantly, if you now take this group, right?
00:48:15
Speaker
So if you take acute kidney injury or RT, I showed you this data.
00:48:19
Speaker
Now you take away these folks over here, and you only look at hybrine and acute kidney injury, what you see is that everything gets better.
00:48:29
Speaker
The recovery
00:48:32
Speaker
the liberation from RRT improves from an odds ratio of 2s to 4.
00:48:41
Speaker
And it's highly significant.
00:48:43
Speaker
And the separation between the recovery group and the non-recovery group is even wider.
00:48:50
Speaker
So the biotype actually informs onto the clinical phenotype, which suggests, at least to me, that the biotype is more important.
00:49:03
Speaker
Now, you know, I know this has been a lot of information that I've kind of thrown down here.
00:49:09
Speaker
So, you know, hopefully you'll have an opportunity to sort of let some of this sink in.
00:49:13
Speaker
But I want to put this back into some basic context.
00:49:19
Speaker
In general, I'm loathe to quote Don Rumsfeld, but, you know, here you are.
00:49:23
Speaker
These are known known.
00:49:24
Speaker
So let me just take you through known knowns, things which we know to be true.
00:49:29
Speaker
Endothelial injury is a hallmark of septic shock.
00:49:33
Speaker
I don't think this is a controversial statement.
00:49:36
Speaker
In fact, in some instances, this is part of the definition of septic shock.
00:49:42
Speaker
This is also well-established.
00:49:44
Speaker
Angiotensin-converting enzyme is an endothelial membrane-bound enzyme.
00:49:48
Speaker
If you don't believe me, please look it up in a textbook or in the literature.
00:49:54
Speaker
Sadly, too many of you will go to the Google and find it on Wikipedia, but I guess that's acceptable.
00:50:01
Speaker
But ACE is an endothelial membrane-bound enzyme.
00:50:06
Speaker
Excuse me.
00:50:08
Speaker
ACE dysfunction in septic shock is not a new finding.
00:50:12
Speaker
I didn't show you this in the interest of time, but this is not new.
00:50:17
Speaker
Many investigators in both preclinical and human data have demonstrated that when you get septic shock, you get ACE dysfunction.
00:50:28
Speaker
The elevated renin piece...
00:50:32
Speaker
is been shown by various investigators previously.
00:50:37
Speaker
And I think that Jean-Louis and Jacques Couture's group in Brussels with this Gleason data have really done a really beautiful study to show not only has it been shown previously, but it's very stable.
00:50:51
Speaker
And we know from all the data surrounding the development of angiotensin-converting enzyme inhibitors that ACE inhibition causes an increase in both renin and angiotensin I. And we know that if you give angiotensin II to a person with ACE inhibition, there is biofeedback, and you can reduce the renin and the angiotensin I.
00:51:20
Speaker
All that I think that we're saying here in this synthesis is all of this is happening in vasodilatory shock as well.
00:51:31
Speaker
It may not be 2 plus 2 is 4.
00:51:36
Speaker
I think it's more that 2 plus 2 plus 2 plus 2 plus 2 plus 2 is 12.
00:51:44
Speaker
None of what I have shown you
00:51:49
Speaker
is something that is a brand new concept that has never been put together any meaningful way.
00:51:56
Speaker
I think what we've been able to demonstrate, which is very new and very important, is the suppressibility of both rene and angiotensin 1 in the shock patient, which is what is the critical glue that puts this entire puzzle together.
00:52:15
Speaker
Now, I don't think many of you believe me.
00:52:18
Speaker
I am quite confident that many of you have listened to this WebEx, for those of you who've hung in as long as you have, and you're thinking to yourself, there's no way this is the way that it is.
Practical Renin Measurement
00:52:28
Speaker
Basically, what you're saying is that when you're in septic shock, you get endothelial dysfunction where ACE lives, and you basically took a big enalopril dose in an environment where you're already hypotensive.
00:52:37
Speaker
And that's, you know, in really simplistic terms, the case.
00:52:41
Speaker
And it can't be that simple or it can't be that obvious, whatever it can't be or shouldn't be.
00:52:45
Speaker
I know that people don't believe this is the way that it is.
00:52:48
Speaker
So here's what I suggest you do.
00:52:50
Speaker
I suggest you start measuring renin by yourself.
00:52:56
Speaker
It's a $5 test.
00:52:57
Speaker
A 96-well ELISA go online for renin.
00:53:00
Speaker
96 wells is around $350.
00:53:02
Speaker
That's less than $5.00.
00:53:11
Speaker
The test.
00:53:13
Speaker
When you have a patient and they're in shock and they have acute kidney injury, measure a renin level.
00:53:22
Speaker
You tell me if it's elevated.
00:53:28
Speaker
Then give whatever goofy intervention you want to give.
00:53:32
Speaker
You want to give more crystalloid and try and create another saltwater drowning in a modern ICU?
00:53:37
Speaker
Knock yourself out.
00:53:38
Speaker
You want to give another catecholamine?
00:53:41
Speaker
Right?
00:53:41
Speaker
They're already on like 100 of norepi.
00:53:43
Speaker
You're going to add epi to find that alpha receptor that's a witness protection in the amygdala?
00:53:48
Speaker
Knock yourself out.
00:53:49
Speaker
Vasopressin, you want to be really tough, really cool, go from 0.04 to 0.06 and go to 0.08, knock yourself out.
00:53:56
Speaker
You want to try some vitamin C, you want to try some methylene blue, some B12, one of each of the primary colors of the voodoo jungle, knock yourself out.
00:54:05
Speaker
And then tell me what happens to the renin levels.
00:54:09
Speaker
Is any of this voodoo working?
00:54:10
Speaker
Is any of this voodoo helping you get the patient better?
00:54:14
Speaker
You don't need to believe anything that I've shown you.
00:54:18
Speaker
Angiotensin 2 is an approved drug in the United States of America and Europe.
00:54:22
Speaker
Renin is a cheap, accessible test.
00:54:24
Speaker
Do it for yourself.
00:54:26
Speaker
Tell me if this is real or not.
00:54:27
Speaker
You can come back to us and say, yeah, you guys are full of it.
00:54:31
Speaker
Let's see if this holds up.
00:54:34
Speaker
And when you do measure the renin, and if it comes back high, this is my exclusive request.
00:54:45
Speaker
Ask yourself, why is it so high?
00:54:49
Speaker
Is it because you didn't give them enough saline?
00:54:53
Speaker
You didn't waterboard them enough?
00:54:56
Speaker
Is it because they're not on enough catecholamine?
00:54:59
Speaker
They're not on enough antibiotic?
00:55:05
Speaker
Why is the renin so high?
00:55:10
Speaker
Or might it be because
00:55:13
Speaker
of an angiotensin-converting enzyme defect due to anethyl dysfunction.
00:55:22
Speaker
And if you didn't promptly intervene with angiotensin II for that patient, ask yourself, in a hybrine and shock patient, if you had to take care of that patient again, would you do something different?
00:55:42
Speaker
Ask yourself, did you do everything that you possibly could have for that patient?
00:55:47
Speaker
Because I would argue that in a high-renin shock patient, they deserve a prompt intervention that deals in the RAS system.
00:56:02
Speaker
That is the only, in my view, reasonable conclusion that one can arrive at.
00:56:09
Speaker
And I'll show you a recent case to try and illustrate this.
00:56:12
Speaker
This is provided to me from a friend of mine named John Chow.
00:56:17
Speaker
He had a 60-year-old gentleman with ESRD who came to the hospital to get a renal transplant, received his allograft, and quite sadly came out of the operating room infected and profoundly vasoplegic.
Case Study: Angiotensin II Effectiveness
00:56:31
Speaker
They ended up crowing out Morganella and Morgani in the patient.
00:56:34
Speaker
And despite the methylene blue hydroxycobalamin,
00:56:38
Speaker
Steroid vasopressin and epi was still quite sick, but he began to get a little bit better, remained in shock, and unfortunately lost his allograft, which was not entirely surprising given all the shock, started showing signs of acute rejection, and was on renal replacement therapy and high-dose vasopressors.
00:56:59
Speaker
This patient was on vasopressors for five weeks.
00:57:06
Speaker
Five weeks, the patient was in shock.
00:57:09
Speaker
And John decided to check a renin level.
00:57:12
Speaker
And he checked a PRA, which was all they really had, which I think is okay.
00:57:16
Speaker
I think a direct renin level is better, but, you know, not one to complain here.
00:57:21
Speaker
And it was 53.
00:57:22
Speaker
The upper lip of normal is 2.
00:57:24
Speaker
That's 25 times the upper lip of normal.
00:57:29
Speaker
It's pretty high.
00:57:32
Speaker
he managed to acquire angiotensin II for the patient, and I'll show you the results.
00:57:36
Speaker
So this is the patient in question.
00:57:39
Speaker
They've been in shock now.
00:57:40
Speaker
So this is the vasopressin dose here.
00:57:43
Speaker
This is the norepinephrine dose here, up as high as 0.8.
00:57:47
Speaker
This is over a period of 35 days consistently on norepinephrine and vasopressin, and receives angiotensin II here, and I'll blow this up so you can see a little more clearly.
00:58:01
Speaker
So now the patient gets angiotensin II with 20 nanograms per gage per minute.
00:58:07
Speaker
The patient becomes immediately hypertensive.
00:58:12
Speaker
The norepinephrine dose and vasopressin dose go to zero, to zero in four minutes.
00:58:24
Speaker
Been in shock for five weeks, off norepinephrine and vasopressin in four minutes.
00:58:31
Speaker
The angiason 2 dose gets turned down from 20 to very close to a physiologic background dose, which the physiologic background dose is 5.
00:58:41
Speaker
There's about 10.
00:58:44
Speaker
And this is what happens to the PRA.
00:58:46
Speaker
It starts at 53.
00:58:48
Speaker
In three hours, it drops by over 50%, identical to the ATHOS-3 data, which is a little bit more than 50%.
00:58:59
Speaker
Within 24 hours is under 10.
00:59:02
Speaker
The upper level of normal for the PRA is 2, so pretty close to normal and stays suppressed.
00:59:08
Speaker
Within 48 hours, the patient who had been on TPN was now tolerating PO.
00:59:15
Speaker
The patient who had been on CRT and they couldn't take volume off, they were able to get the patient negative.
00:59:21
Speaker
and were able to switch to intermittent hemo.
00:59:24
Speaker
And within three days, after being in the ICU for five weeks in shock, went to the floor off of all vasopressors.
00:59:34
Speaker
What if they had just let this guy be in shock with vasopressin and norepinephrine for another five weeks?
00:59:45
Speaker
So in my view, there's more than just the clinical opportunity to make someone better, which I think is obviously hugely important.
00:59:54
Speaker
But if you look at the curves, what you see is that angiotensin II in the high renin arm restores you back to the low renin group.
01:00:02
Speaker
I think there's an opportunity to bring these people back.
01:00:04
Speaker
And let me explain what I mean in a little more clarity.
01:00:10
Speaker
It's my view that many of the old drugs, in fact, work.
01:00:16
Speaker
I was a fan of activated protein C. I think activated protein C worked.
01:00:21
Speaker
I think that other drugs have a capacity to work.
01:00:24
Speaker
And I think that these high renin vasoplegic patients may be part of the reason why we don't get consistent results.
01:00:33
Speaker
And let me walk you through some of my thinking.
01:00:37
Speaker
So imagine you're running a large randomized control trial.
01:00:39
Speaker
You have an active arm, and you randomize them to protein C, early gold rectotherapy, alkaline phosphatase, steroids, whatever.
01:00:48
Speaker
Within both arms of your septic shock trial, you are going to get a bunch of high renin shock patients.
01:00:54
Speaker
They may or may not be balanced.
01:00:58
Speaker
You may get unlucky, and they get imbalanced.
01:01:01
Speaker
The problem is, is these people dampen your effect.
01:01:05
Speaker
These folks don't get better.
01:01:07
Speaker
They have a very high mortality.
01:01:10
Speaker
They have high levels of endothelial dysfunction, which we measured and looked at.
01:01:14
Speaker
I didn't have time to show you those data.
01:01:17
Speaker
And they become catecholamine-resistant.
01:01:22
Speaker
So they just die.
01:01:24
Speaker
Well, if you then say to yourself, well, this dampening of the signal by hyarine and shock
01:01:31
Speaker
Well, how can you figure that out?
01:01:33
Speaker
Well, I think a simple thing to do is if you have biobank samples or in a future trial, look in the low renin arm.
01:01:41
Speaker
And in the low renin arm, I'll bet you a lot of these interventions work.
01:01:48
Speaker
And if they work in the low renin arm and you can show that, then if you add angiotensin 2 in the high renin arm and you add that other agent, it should help them even more.
01:02:01
Speaker
And what I am proposing is that if high renin is a biotype, then understanding what low renin patients are is as important as knowing what to do for high renin patients.
01:02:21
Speaker
So in conclusion, we confirm that
01:02:28
Speaker
that elevated renin shock is associated with a worse survival and severe AKI.
01:02:34
Speaker
And I want to make this very clear.
01:02:35
Speaker
This is a confirmation because elevated renin and outcomes has been in the literature since 1983.
01:02:42
Speaker
The cutoff for this dichotomization and for the most informative improvement is around three times your level of normal of whichever renin assay you're using.
01:02:57
Speaker
Elevated renin shock is a biotype for shock, and it's also an AKI biotype.
01:03:08
Speaker
Angiotensin II infusion effectively suppresses both renin and angiolone.
01:03:13
Speaker
This strongly suggests that the angiotensin-converting enzyme defect is driving this effect.
01:03:23
Speaker
And the insufficient ATR1 receptor engagement is the reason for the high renin in the first place, because nothing else pushes it down.
01:03:35
Speaker
And the Gleason data show that renin is a better predictor of ICU survival than lactate.
01:03:45
Speaker
And now you have an agent that allows you to bring that down.
01:03:50
Speaker
And we have shown you that that identifies patients who gain survival benefit.
01:03:58
Speaker
This biotype improves outcomes in elevated renin shock, AKI.
01:04:02
Speaker
We also did it in ARDS.
01:04:04
Speaker
So, elevated renin is an ARDS biotype as well.
01:04:08
Speaker
I didn't have time to show you those data, but that's what we've looked at in our set, and it's there.
01:04:15
Speaker
And serum renin is inexpensive.
01:04:18
Speaker
It's widely available.
01:04:20
Speaker
And I think this is going to allow us to personalize the care, guide vasopressor care to those patients who gain the maximum survival benefit, and importantly, benefit in those patients who have severe acute kidney injury.
01:04:39
Speaker
And my prediction is,
01:04:41
Speaker
that within two years, serum renin will replace FINA in patients with shock and AKI.
01:04:47
Speaker
I would argue that measuring FINA in a patient who is already in shock and on vasopressors and on 10-plus liters of crystalloid is a terrible idea because if it ends up being low, it'll be an excuse for some intern to give more saline to a patient who is already succumbing to a saltwater drowning in the intensive care unit.
01:05:11
Speaker
But that is a rant for another time.
01:05:14
Speaker
And with that, for those of you who've hung in here for the duration of this talk, I'll move to questions.
01:05:20
Speaker
And I would like to thank Sergio again for the opportunity to share with you guys some new data.
01:05:24
Speaker
And hopefully, these data will be published in the very near future.
01:05:29
Speaker
Thank you.
01:05:32
Speaker
Excellent.
01:05:32
Speaker
So we've concluded with the video.
01:05:35
Speaker
I know that we've had some technical difficulties, but I did get some questions.
01:05:41
Speaker
text it to me, Mink, and I think that we can go ahead and maybe entertain some of those.
01:05:46
Speaker
And first, I think that thanks for sharing all this new data with us.
01:05:51
Speaker
I think a lot of very exciting information that I'm sure is going to be published very soon, and I think that hopefully will really transform the way we start thinking about these patients.
01:06:05
Speaker
But I would like to start, Mink, if it's okay, with some physiopath questions
01:06:10
Speaker
that I think are of interest.
01:06:13
Speaker
And you did talk about the biotype versus the clinical phenotype.
01:06:18
Speaker
The other question that I was going to ask you is, is this high renin biotype a different pathway, or is it just, I mean, a severity of disease, and patients who might not be as sick enough just don't manifest it?
01:06:34
Speaker
Yeah, so that's a great question.
01:06:36
Speaker
And, you know, I think that
01:06:38
Speaker
The answer is from the ATHOS data alone, I don't think we can say with 100% certainty which one it is.
01:06:43
Speaker
But in my view, it's almost certainly a biotype, not just severity of illness.
01:06:47
Speaker
So if you look at the multivariate regression, we take into account Apache, low blood pressure, norepinephrine dose, and it still holds up dramatically with a really impressive hazard ratio of 0.59, which gives you a 41% reduction.
01:07:07
Speaker
in mortality and its improvement in survival despite those features.
01:07:11
Speaker
And so it's my suspicion that certain patients develop a more severe endothelial type of injury.
01:07:20
Speaker
And I'm sure that some component of this is their genetic background, what they bring to the table, whether they were primed for an inflammatory hit.
01:07:28
Speaker
I think all these things contribute.
01:07:30
Speaker
And then I think my view, probably what happens is
01:07:34
Speaker
you hit a critical point of endothelial injury where your body paints itself into this corner.
01:07:40
Speaker
So it's vigorously trying to make more and more angiotensin 1 by increasing the renin.
01:07:46
Speaker
And that angiotensin 1, instead of going to angiotensin 2, gets shunted into this vasodilatory pathway, and it just makes everything worse.
01:07:54
Speaker
And the reason why I think this is the case is because, you know, this is a piece of trivia, but it's been weighing on me for a long time, which is that
01:08:03
Speaker
The first ACE inhibitor was discovered in the venom of a Brazilian pit viper.
01:08:08
Speaker
And so from an evolutionary standpoint, nature has figured out a very, very long time ago that a very effective way to kill a mammal is to take away its ACE function quickly.
01:08:18
Speaker
And, you know, if you take that poison, which is where ACE inhibitors were actually developed from that finding of an ACE inhibitor in venom, and you decrease the dose by a thousand fold, you get captopril.
01:08:30
Speaker
But,
01:08:32
Speaker
anyone who's seen a patient with an ACE inhibitor overdose knows what profound catecholamine refractory hypotension looks like, and those folks do quite badly.
01:08:42
Speaker
And so I think that this is something which the body does not prepare itself well for.
01:08:48
Speaker
And when you hit that critical threshold of an endothelial injury, you get trapped into this vasoplegic, you know, ACE defect corner.
01:08:59
Speaker
Are there patients that, you talked about the clinical phenotype of the high renin.
01:09:05
Speaker
Are there patients who have normal renin that still need dialysis?
01:09:11
Speaker
And in those patients, do we know, I mean, the effect of Agitensin II?
01:09:16
Speaker
Yeah, so what's interesting is that if you look at the subset of the high renin and AKI, most of the benefit is there.
01:09:24
Speaker
And so AKI alone,
01:09:27
Speaker
isn't enough because the benefit is in the high renin patients.
01:09:30
Speaker
So the answer is yes, there are patients who have AKI who have low renin and there are patients who have high renin shock who don't have AKI yet.
01:09:38
Speaker
So that's why I think the biotype is the future because we, I think, can reach a point where we can dial in the correct vasopressor, at least one of the vasopressors based on available measures of physiology.
01:09:53
Speaker
So in a perfect world,
01:09:56
Speaker
you would use as of now the renin level as a better discerner of who an agitantism to might be helpful.
01:10:07
Speaker
Yes.
01:10:07
Speaker
And so I think the issue, yeah, that's right.
01:10:10
Speaker
So the issue now is that most hospitals in the country, the turnaround time is it's send out.
01:10:17
Speaker
And I think that a lot of hospitals can get it back within 36 hours.
01:10:22
Speaker
And so I think it's very similar to the blood culture.
01:10:25
Speaker
where if you have a patient who has a clinical phenotype, you can start them on broad spectrum vasopressors, similar to broad spectrum antibiotics, and then you get your renin level back.
01:10:37
Speaker
And if it's below three times your blue abnormal, you deescalate.
01:10:41
Speaker
And this is a very efficient way to give your patient the best chance of surviving and mitigating costs by using the vasopressor in a highly biologic fashion.
Future of Shock Treatment
01:10:52
Speaker
I think that's the future.
01:10:53
Speaker
We wrote a paper
01:10:55
Speaker
that came out about six months ago called broad spectrum vasopressors.
01:10:58
Speaker
Ironically, at the time, we didn't have the renin data, otherwise I would have put it in that paper.
01:11:03
Speaker
We said, you know, I think broad spectrum makes sense, and then we need to find the markers that tell you what to do, and it just so happened that that analysis came back a few weeks later.
01:11:11
Speaker
But I think the future is broad spectrum vasopressors, and it wouldn't surprise me in the future that in addition to measuring a lactate and getting a blood culture, you would get a vasopressor sensitivity panel
01:11:24
Speaker
and start broad-spectrum beta suppressors and then de-escalate this appropriate.
01:11:30
Speaker
And can you, I've never used renin, but I'm sure that in the nephrology world, like you said, it's not a new assay.
01:11:36
Speaker
People have ordered it.
01:11:37
Speaker
So this is something that clearly you have mentioned.
01:11:40
Speaker
It's not an expensive test.
01:11:42
Speaker
It's not maybe something that has a rapid turnover and hospitals can get it.
01:11:47
Speaker
Is the range usually within the similar ranges or the different assays that people use and we should just use the 3X?
01:11:53
Speaker
Can you give us a little bit more
01:11:54
Speaker
of the practical aspect of it, Mink?
01:11:57
Speaker
Yeah, that's a good question.
01:11:58
Speaker
So the serum renin test that we used had a normal range of 5 to 50, and that's pretty consistent with most serum ranges.
01:12:07
Speaker
If you look at the plasma range, the range is like 2.5 to 25.
01:12:10
Speaker
Of course, the assay differs.
01:12:13
Speaker
I think the easiest thing to do is to take the upper limit of normal and do 3x the upper limit of normal.
01:12:18
Speaker
And, you know, we did a sensitivity analysis, which in the interest of time I didn't put up here because it's kind of complicated.
01:12:24
Speaker
If you are looking for a pure value decision on where you get the maximum survival benefit, it's above the 3x, above normal.
01:12:34
Speaker
So for instance, take any direct assay you have.
01:12:37
Speaker
Let's say your lab runs assay 42, whatever that is.
01:12:42
Speaker
And the assay in your lab comes back and the normal range is 10 to 60.
01:12:48
Speaker
Well, that means that if the patient has a value above 180, that's someone who
01:12:54
Speaker
is going to get a survival benefit from angiotensin too.
01:12:56
Speaker
Because even though these assays don't have the exact same normals, they all scale very similarly.
01:13:02
Speaker
Okay.
01:13:03
Speaker
And I think that ultimately, right, as people perhaps are using this more and we learn more about how to apply it at the bedside, I would imagine that if it's not a complicated test, turnover time can come quicker and it might be a lot easier to do it at institutions that use it a lot in a much quicker fashion.
01:13:22
Speaker
Yeah, I expect that very large institutions that have the throughput for this, they'll be able to, they probably will move away from a central lab and they'll do it in-house and they can get it back in 24 hours.
01:13:34
Speaker
And there'll be a very fast blood culture, which I think would be great.
01:13:37
Speaker
And that would be a phenomenal place to be.
01:13:40
Speaker
I mean, I think for smaller hospitals that don't have it, waiting two days is maybe too long.
01:13:45
Speaker
I think it's not terrible.
01:13:47
Speaker
Five days is too long.
01:13:48
Speaker
So I think clinicians are going to say, look, if it is a sundown, we get it.
01:13:52
Speaker
but we do want it back in timely fashion because you wouldn't want to wait for a MRSA blood culture for five days.
01:13:57
Speaker
I think similarly waiting for your vasopressor sensitivity assessment for five days is too long.
01:14:03
Speaker
So I think getting it within 48 hours is minimum.
01:14:06
Speaker
I think within 24 to 48 is ideal.
01:14:07
Speaker
Okay.
01:14:10
Speaker
So let me ask you a bedside question, and then I would like to move maybe into more of hospital bedside.
01:14:20
Speaker
PNT type of questions of getting your input on how to get new drugs on formulary, what are the things that we can do at our different hospitals?
01:14:29
Speaker
So if I had a patient who comes in and I'm suspecting a vasodilatory shock, let's say from sepsis, as I give volume, I should start probably giving my vasopressors very quickly.
01:14:45
Speaker
I think most people would agree that norepinephrine would be the first line.
01:14:50
Speaker
If I'm escalating that or not getting the MAP that I want, I would add a second drug.
01:14:55
Speaker
Perhaps if somebody had renal failure, that would be angiotensin 2 or in many places might be vasopressin.
01:15:04
Speaker
But very quickly thereafter, I would be adding a third drug if the patient was not doing well.
01:15:09
Speaker
And I guess the idea that we have discussed previously on some of the podcasts we did together is that it just makes sense to treat with a different type of drug as opposed to
01:15:19
Speaker
adding more catecholamines.
01:15:21
Speaker
So obviously angiotensin II would be the obvious next phase.
01:15:25
Speaker
And at that point, you would be sending hopefully a renin test and treating the patient.
01:15:32
Speaker
And whatever the turnover is, hopefully what you would see is that the renal function improves, you wean down the vasopressin, you wean down the norepinephrine, and if you get the renin test before that and it's high, you probably would continue with the angiotensin II
01:15:48
Speaker
If you get it back and you did really well, maybe the patient's out of shock, but you at least have an answer, right?
01:15:54
Speaker
Is that the way you would approach it at the bedside, Ming?
01:15:56
Speaker
Yeah, I think that's exactly right.
01:15:57
Speaker
And I think that the important thing to remember is there is also this notion of
01:16:03
Speaker
excuse me, of the order, whether it's catecholamine first, then ANG2, or catecholamine, then vasopressin.
01:16:10
Speaker
Much of that is driven by habit.
01:16:12
Speaker
But I think the other big question is how sick is the patient, right?
01:16:15
Speaker
And you get a feel for that in an ICU physician.
01:16:17
Speaker
You come in, you give them a little bit of norepi, they settle out, they're a little bit higher, you're like, okay.
01:16:23
Speaker
But there are patients that are clearly evolving rapidly in front of you.
01:16:27
Speaker
And in those patients,
01:16:29
Speaker
Because the pharmacists are very aggressive at trying to manage the budget, they will say, well, you got to wait until they're on 0.5 of Norep B before you give it, or you got to wait until they're on 24 hours, show me that they're refractory.
01:16:40
Speaker
That to me is insanity.
01:16:42
Speaker
That's like trying to decrease your TPA bill by only giving TPA for stroke after three hours.
01:16:49
Speaker
I mean, this kind of behavior I find profoundly offensive.
01:16:54
Speaker
And then you end up using whatever the drug is, in this case, it's antigenotensin too, late.
01:16:58
Speaker
And people say, oh, it didn't work.
01:17:00
Speaker
I mean, so just so we're clear, it doesn't work in dead people.
01:17:03
Speaker
The trade name is Geopressa, not Liquid Jesus, right?
01:17:06
Speaker
So it's very important people understand that if you're going to do this, you do it early and you do it promptly.
01:17:12
Speaker
It doesn't mean you're first line, but it means you're extremely prompt.
01:17:16
Speaker
I think checking a REAN level is how you demonstrate value.
01:17:21
Speaker
And you can say, look, this is a survival benefit, but more than that,
01:17:25
Speaker
You know, CRRT costs $4,000 a day all in.
01:17:29
Speaker
Intermittent hemo is like $1,500 a day.
01:17:32
Speaker
But take the money aside for a second and look at as intensive as, you know, managing the budget and helping keep costs down as part of your job.
01:17:40
Speaker
But I assure you, if you get someone off of dialysis, you've saved the patient something they don't need and you don't want for them.
01:17:47
Speaker
But you save the entire healthcare system huge dollars, right?
01:17:52
Speaker
And the hospitals get a save
01:17:54
Speaker
without dialysis, which saves them money.
01:17:56
Speaker
So now that we know and we have a biotype that localizes on this expensive thing, which is acute kidney injury, I think that this is the critical intellectual approach to move forward and more importantly, to gain benefit.
01:18:15
Speaker
So we ran at those with the idea that we're gonna do a MAP study.
01:18:19
Speaker
And everyone's like, oh, it's MAP, it's MAP, what does MAP mean?
01:18:23
Speaker
We did this very intentionally because we said we're gonna run a MAP study so we can show safety and efficacy as a vasopressor and then we're gonna look very hard to find a way to inform clinicians on a way to select the patients in whom there's benefit.
01:18:40
Speaker
And I think clinicians have been asking us, do you have something simple and easy to do?
01:18:44
Speaker
And the answer now is yes.
01:18:46
Speaker
I think the rubber hits the road now to see who was just talking and asking for more and never planning on doing anything.
01:18:52
Speaker
and who's going to see the potential of this opportunity and deliver it to patients and the healthcare system to get better outcomes.
01:19:01
Speaker
And I think that the other thing that for me is very interesting after hearing this new set of data that you share with us is that when we first spoke about this, you had identified
Importance of Early Angiotensin II Administration
01:19:13
Speaker
or you already had new and the paper has been published of that benefit in the particular subgroup of renal failure patients, right?
01:19:22
Speaker
And it now seems that the reason why in that clinical phenotype, at least the way I interpreted it, it was so positive is because the vast majority of them have a renin problem, right?
01:19:33
Speaker
So truly the renin that we're identifying or is the real marker, the biomarker that we should be thinking of and trying to identify.
01:19:41
Speaker
And the second point or question I have at Mink is, which I think is important, early is very, very important with any time sensitive therapy.
01:19:50
Speaker
So obviously you want to start these therapies early, like you said, not when the patient's dead.
01:19:55
Speaker
But in terms of timing, if the patient's on RRT, you still should start it.
01:20:02
Speaker
I mean, it's not like, oh, they're on RRT, now there's no point, right?
01:20:05
Speaker
Because you might get them off the RRT if I understood the data correctly quicker.
01:20:10
Speaker
Yeah, so that's exactly right.
01:20:11
Speaker
And I will tell you that, you know, this has been one of the biggest surprises of my career.
01:20:16
Speaker
is I'm an AKI researcher, and I have been telling my fellows, and I go to big meetings and talk on podiums, and I tell everyone, and I have been telling people for many, many years, when you're on dialysis, it's too late.
01:20:28
Speaker
You have to use the AKI biomarkers.
01:20:30
Speaker
I did a lot of work on the Nefrocheck biomarker with John Kellum, and we're telling everyone early, early, early for AKI.
01:20:36
Speaker
And so
01:20:37
Speaker
The person who is the most stunned that you could be in shock and on dialysis and still show something worked to get you off dialysis was me since I have been preaching the opposite for 15 years.
01:20:49
Speaker
So you know when you're preaching something and then it blows up in your face in a good way, you pay attention to it.
01:20:57
Speaker
If they have AKI and they're on dialysis, that is the patient you need to get in on.
01:21:02
Speaker
And you have to push people because if you don't, if you wait 10 days on dialysis, I mean, please, I mean, you know, how many times, how long do you think a kidney can hold up?
01:21:10
Speaker
I mean, it's stunning to me that people think that you can wait so long and cells come back.
01:21:15
Speaker
But you can turn this around because it's a hydraulic phenomenon of a defect or a diminishment of angiotensin II effect and probably elevated angiomone to seven.
01:21:24
Speaker
And you can fix that quickly.
01:21:26
Speaker
And those hydraulics come back quite quickly.
01:21:28
Speaker
And if you look at the curves that I showed you in the talk,
01:21:32
Speaker
you see the separation between recovery happens very quickly.
01:21:35
Speaker
The curves begin to separate within one day.
01:21:38
Speaker
So there's a handful of patients who respond almost immediately.
01:21:41
Speaker
So in my mind, shock and AKI going on RRT, or as you're thinking about putting a Quentin in, or as you're beginning to flog that mild-loop diuretic, that is an opportunity to turn that patient around.
01:21:52
Speaker
Yeah.
01:21:54
Speaker
And I think that early, obviously, is always better, but rather...
01:22:00
Speaker
late than never as that data you showed us of the poor patient who was in shock for 35 days, right?
01:22:07
Speaker
So there's always opportunity to act and I think it's just kind of- That was incredible.
01:22:11
Speaker
Yeah.
01:22:12
Speaker
Yeah.
01:22:12
Speaker
I got to tell you when he, Jonathan called me and he's like, this patient's been in shock for, you know, 30 days.
01:22:17
Speaker
I thought he was joking.
01:22:19
Speaker
I mean, I've never taken care of a patient who survived 30 days in shock.
01:22:22
Speaker
I mean, 10 days is like a lot.
01:22:25
Speaker
But, you know, I shall be honest with you.
01:22:27
Speaker
Like Jonathan, who's at the University of Maryland, is this super talented, bright guy.
01:22:31
Speaker
I didn't believe him.
01:22:33
Speaker
I didn't believe him until he showed me the slides that I shared with you guys.
01:22:37
Speaker
And I was like, he is not lying.
01:22:39
Speaker
This person has been on Norepi for 13 plus.
01:22:43
Speaker
I mean, I was stunned.
01:22:44
Speaker
And then the fact that he went off all of it in three minutes was like, that is pretty dramatic.
01:22:50
Speaker
But that's the exception, not the rule.
01:22:53
Speaker
I don't want your...
01:22:55
Speaker
the folks in Salem to think, oh, you know, I will waltz in after I go on vacation for 30 days and come back and put Mr. Jones on it.
01:23:02
Speaker
Yeah.
01:23:05
Speaker
So that would be a bad approach.
01:23:07
Speaker
Well, and I think that really the other part that is obviously extremely interesting of all this is that, like you said, I mean, a lot of these, a lot of the data or a lot of the concepts have been studied and shown elsewhere.
01:23:22
Speaker
These are not necessarily new
01:23:24
Speaker
new discoveries, but it's all putting it together in a different context that makes it so interesting.
01:23:30
Speaker
And it's almost like the puzzle.
01:23:32
Speaker
You keep adding pieces and now you can see the picture, which I think is pretty cool and pretty encouraging.
01:23:39
Speaker
But the practical questions I have for you, Mink, is a lot of our hospitals don't have ANG2 on their formulary as of yet.
01:23:50
Speaker
And in the current environment,
01:23:53
Speaker
it's a lot harder to get new drugs on board, especially when there's a cost concern.
01:24:00
Speaker
So are there any suggestions or any tips or anything that you can share with us that might be of use for intensivists who are listening to this and who are now interested in bringing this to their patients?
01:24:15
Speaker
Yeah, so I think that's a great question.
01:24:16
Speaker
I'll tell you what we did at GW when I was there.
01:24:20
Speaker
And it's that at the end of the day, it's going to be about cost for the hospital.
01:24:25
Speaker
They're terrified about new drugs and expenses.
01:24:27
Speaker
And I think that there has to be a conversation that says, we know you're worried about this new drug and it appears to be expensive to you.
01:24:36
Speaker
It's not CAR T therapy, which is 500 grand therapy.
01:24:38
Speaker
This is $1,500 a day.
01:24:40
Speaker
It's a course therapy is $3,000 roughly.
01:24:43
Speaker
It's cheaper for a lot of hospitals in the country.
01:24:46
Speaker
And the way you make the conversations, you say, look, we use a lot of vasopressin that doesn't work.
01:24:52
Speaker
Half the time you get vasopressin, there's no blood pressure effect.
01:24:54
Speaker
And so you say, look, show us the vasopressin budget, and we're going to be really good about turning it off when it doesn't work.
01:25:02
Speaker
That's going to create room in the budget to make sure that we can address and have a vasopressor that works on this pathway.
01:25:10
Speaker
for which nothing else works.
01:25:11
Speaker
We have no other options and for a patient who has a high renin shock defect, there's nothing you can do, you can fix them.
01:25:18
Speaker
More norepinephrine is not gonna fix it.
01:25:21
Speaker
And this take home point here is that this vasopressor is more than MAP.
01:25:28
Speaker
Getting MAP with norepinephrine to 65 or 70 versus getting a MAP of 65 or 70 with ANCH2 is not the same
01:25:39
Speaker
in a high reading patient, because in a high reading patient, you're addressing their defect.
01:25:44
Speaker
Arguably with norepinephrine, you're making it worse because it causes pre-capillary sphincter basic constriction and exacerbates endothelial injury.
01:25:51
Speaker
So you may make yourself feel better by looking at the macro-human dynamics get better.
01:25:56
Speaker
But as you're doing that and trying to make yourself feel better, keep your hand on the patient's toe.
01:26:01
Speaker
As your big toe becomes white and cold, you can ask yourself if you're doing this patient a favor or not.
01:26:08
Speaker
Fundamentally, I think if you understand physiology, you have to have this available.
01:26:14
Speaker
Now, I think in order to convince your pharmacist, you have to be responsible about it.
01:26:19
Speaker
You can't give it to dead people and you have to find a way to make room for it in the budget.
01:26:24
Speaker
And this is done.
01:26:26
Speaker
But the truth of the matter is, Sergio, is that intensivists are so beaten down by coming in, all the charting, all the Epic and Cerner and all the pain with the medical record,
01:26:37
Speaker
and everything else they need to do, they've kind of lost their will to fight.
01:26:41
Speaker
And they'll go in and ask the pharmacist and say, I really need it.
01:26:43
Speaker
The pharmacist says, no.
01:26:44
Speaker
And they just say, okay.
01:26:45
Speaker
And they roll over.
01:26:47
Speaker
And so what I would ask anyone who's listening to this is, like I said, I don't want you to believe me.
01:26:52
Speaker
I want you to start measuring renin levels in your shock patients.
01:26:56
Speaker
I want you to see what these numbers are.
01:26:58
Speaker
And then you decide if you decide that it's worth the fight to have this for your patients or not.
01:27:04
Speaker
Yeah, and what would also, I think, be very interesting is to see what, in terms of pathophysiology standpoint, the point you made on catecholamines is that it's true that we keep flogging people with the same of the more that may not be helping them at the end, and that we were to be able to measure levels.
01:27:24
Speaker
Most patients in shock probably have high catecholamines.
01:27:26
Speaker
That's the whole point, right?
Risks of Excessive Catecholamine Use
01:27:28
Speaker
But we're just giving them more of what they have and not more of what they don't, and that that's where I think might be the difference.
01:27:36
Speaker
I think that's right.
01:27:36
Speaker
And I also think that if you recognize that low-dose catecholamines really help you in shock.
01:27:42
Speaker
When you start getting the high-dose catecholamines, you're getting the toxicity.
01:27:46
Speaker
And no one treats hypertension.
01:27:48
Speaker
If you fail 100 milligrams of BID of metoprolol, no one puts you on a gram of metoprolol.
01:27:53
Speaker
Even though that will bring your blood pressure down.
01:27:56
Speaker
It'll make your heart rate two, but your blood pressure will be better.
01:27:59
Speaker
So we don't do that because it's profoundly anti-intellectual.
01:28:03
Speaker
So when I meet clinicians who say norepi is enough, I usually write down the name of that hospital and I try to make sure no one gets sick near there because that's a profoundly dangerous approach to shock in my view.
01:28:15
Speaker
Yeah, absolutely.
01:28:18
Speaker
So we have another question from the audience regarding any experience or data you could share with us in CKD patients.
01:28:26
Speaker
Yeah, so we did not break out CKD separately in the adathose 3 trial.
01:28:30
Speaker
And a lot of this is because we did not have access to baseline creatinins.
01:28:36
Speaker
It's my suspicion that not just CKD, but what happened to you with your CKD is going to matter.
01:28:44
Speaker
Lots of CKD patients are ACE inhibitors.
01:28:46
Speaker
ACE inhibitors have very long half-lives.
01:28:48
Speaker
Most people don't know this, but ACE inhibitors are pro-drugs.
01:28:51
Speaker
So they have half-lives at 50 hours or so.
01:28:53
Speaker
So if they were taking an ACE inhibitor,
01:28:56
Speaker
and then they got sick, or an A2 blocker, and then they got sick, that drug is still in their system.
01:29:01
Speaker
And so A2 helps ameliorate both patients on ACE inhibitors and A2 blockers, although the A2 blocker part's a little bit counterintuitive.
01:29:10
Speaker
We have had patients who have been on high-dose A2 blockers and overdoses, and they respond to ANG2, so we know it works.
01:29:17
Speaker
And there's the background that CKD patients tend to have more ACE expression on their endothelium.
01:29:24
Speaker
And so how that translates in a shock state, we just don't know at this point.
01:29:29
Speaker
And I think one of the things which is exciting with this discovery, frankly, is there's so much left to learn, right?
01:29:37
Speaker
This is just the beginning.
01:29:39
Speaker
This is okay.
01:29:39
Speaker
We have the beginning of a subtype of a group and that's really good, but we really need to understand all these parameters and there's a lot more work to get.
01:29:51
Speaker
Absolutely.
Closing Remarks and Gratitude
01:29:52
Speaker
I think that,
01:29:54
Speaker
These are very fascinating developments.
01:29:57
Speaker
I hope that the audience really pushes forward at their institutions to start using this new drug, start learning more about it, checking angiotensin as well, and hopefully we'll have you back, Mink.
01:30:14
Speaker
I mean, you really have been so gracious with your time and expertise.
01:30:18
Speaker
I think that you can either read all the articles on ang2
01:30:23
Speaker
or you can listen to the two podcasts we did, Mink, together and this, and I think you'll have a very good handle of where things stand today, thanks to all the expertise you shared with us.
01:30:34
Speaker
Any parting thoughts for the audience, Mink?
01:30:36
Speaker
Yeah, I just say the one thing is, first of all, thank you very much for the opportunity to show the data I presented at the FACET meeting, you know, about a week and a half ago, so it's public, but I thought this would be a good opportunity to share it with your group.
01:30:48
Speaker
And what I would say is that, you know,
01:30:51
Speaker
One of the things that you guys do as a group is you go into hospitals to create value.
01:30:56
Speaker
And it's not just cost containment value and giving better care.
01:31:00
Speaker
But I'm telling you, if you start using Ange Tooth, Doffoli, and all these systems, right, if you decrease the AKI rates and the CKD rates as a consequence of that and days on dialysis, you want to talk about demonstrating value.
01:31:16
Speaker
That is a huge opportunity.
01:31:18
Speaker
And I would love to see your group
01:31:20
Speaker
look at this and start implementing it across different hospital systems and publish that or at least do a white paper on it and show us what modern, thoughtful, critical care looks like where you are thoughtful about cost, but you still make sure you get the best outcomes and you show people how to demonstrate your value, which I think this gives you.
01:31:42
Speaker
Absolutely.
01:31:43
Speaker
And the last thing I want to thank you is for reminding me of my pharmacology days
01:31:48
Speaker
of reading about ACE inhibition and Goodman and Gilman, and now knowing that I wasted all my time in that very long chapter.
01:31:55
Speaker
It was all wrong.
01:31:57
Speaker
I'll tell you, the thing which is so astonishing is, you know, the day that I was the smartest in my life was the day that I graduated my fellowship, and I was a genius that day.
01:32:07
Speaker
And then every day after that, the universe of what I don't know has expanded 10x compared to what I've learned, which is maybe 10%.
01:32:13
Speaker
So I think you've probably had a very similar experience in your career, and it remains humbling.
01:32:18
Speaker
But yes, everything you learned about how an ACE inhibitor works is actually wrong.
01:32:23
Speaker
Ming, thank you so much for your time again.
01:32:25
Speaker
This was a great, great conversation.
01:32:28
Speaker
Thanks, Sergio.
01:32:29
Speaker
Take care and go Eagles.
01:32:31
Speaker
Thank you.
01:32:33
Speaker
Thank you for listening to Critical Matters, a sound critical care podcast.
01:32:38
Speaker
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01:32:44
Speaker
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01:32:49
Speaker
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