Transcript
Speaker: Welcome to Critical Matters, a sound critical care podcast covering a broad range of topics related to the practice of intensive care medicine.
Speaker: Sound Critical Care provides comprehensive critical care programs to hospitals across the country.
Speaker: To learn more about our programs and career opportunities, visit www.soundphysicians.com.
Speaker: And now your host, Dr. Sergio Zanotti.
Speaker: Welcome to our series of clinical webinars.
Speaker: from Sound Critical Care.
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.
Speaker: So we are going to go ahead and get started.
Speaker: We are having some technical difficulties,
Speaker: So we're going to share a link with the audience.
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.
Speaker: Okay, I'd like to welcome everyone to this talk on personalized selection of vasopressors and the treatment of shock.
Speaker: Sergio, I very much appreciate the invitation to give this WebEx, and I hope to take you through some interesting data.
Speaker: Much of this is currently unpublished, and give you a sense of where we think things might be headed with utilizing
Speaker: biomarkers to help decide which vasopressor might be the most appropriate for patient vasodilatory shock.
Speaker: Importantly, there are some very important key disclosures that you should keep in mind when listening to this talk.
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.
Speaker: And I think perhaps the most important conflict is that
Speaker: I am the most conflicted human on planet Earth for Angiotensin II.
Speaker: I've been working on this product and this peptide for about a decade.
Speaker: And so whenever you have a scientific bias, that becomes something that you need to keep in mind
Speaker: whenever someone who has scientific bias is talking to you.
Speaker: So I'm sure you'll bear that in mind when looking and listening to these data.
Speaker: Nonetheless, I endeavor to give you a very scientific discussion and talk.
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.
Speaker: And really the goal of this trial, which I did at George Washington University Hospital in Washington, D.C.,
Speaker: was to really understand the dose.
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.
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.
Speaker: And so the goal of this trial was safety, can we give the drug safely, and what dose should we give it in?
Speaker: And I'm not going to take you through the pilot trial.
Speaker: I think many of you listening to this have already seen this or at least read this study.
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.
Speaker: such that while on high-dose catecholamines, specifically norepinephrine and vasopressin, when angiotensin-2 was initiated, the patients promptly became hypertensive.
Speaker: All the other vasopressors were completely weaned off.
Speaker: And on physiologic dose replacement, the patients remained hypertensive.
Speaker: And as a consequence of that, and I didn't really anticipate this in my protocol,
Speaker: We reported it as an adverse event.
Speaker: The infusions were stopped prior to the full amount of time that had been allotted.
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.
Speaker: And, you know, it was really extraordinarily striking.
Speaker: You know, you don't see this type of response in clinical medicine that frequently.
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.
Speaker: You know, it was extremely dramatic.
Speaker: And
Speaker: Initially, I had thought this was because these patients had been exposed prior to their critical illness with ACE inhibitors.
Speaker: And that ended up being wrong.
Speaker: They hadn't been exposed to ACE inhibitors, and we were searching to understand why
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.
Speaker: And so what that basically means is that
Speaker: ACE doesn't do most of its work as a free-floating enzyme, although you can measure ACE in the blood.
Speaker: The vast, vast majority of angiotensin-converting enzyme capacity exists on the endothelium.
Speaker: And to a very large degree, it exists on the pulmonary endothelium.
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.
Speaker: And this has been demonstrated previously quite elegantly.
Speaker: This is a very beautiful trial done by Orphanos and colleagues that was published in Circulation in 2000.
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.
Speaker: So this is a molecule that is metabolized by anadrogenase-converting enzyme.
Speaker: And they used this to assess ACE capacity in patients with acute lung injury.
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.
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.
Speaker: The ACE capacity is diminished by severe lung injury.
Speaker: And so...
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.
Speaker: And this was published a few years back in 2016.
Speaker: Basically, the sequence of events is as follows.
Speaker: You have an inflammatory insult, whether it be from trauma, sepsis, a toxin, whatever.
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.
Speaker: And it's not exclusively seen in patients with ARDS.
Speaker: Patients who have endothelial injury very broadly can demonstrate this kind of pathophysiology.
Speaker: And when this happens, what we have proposed is that you develop an angiotensin 2 insufficiency.
Speaker: And this angiotensin insufficiency leads to catecholamine resistance and acute kidney injury.
Speaker: I think for people who have good recall of the way Agitensin II works in the kidney, this is quite obvious.
Speaker: The issue of the catacombin resistance, interestingly, is not well appreciated by many.
Speaker: And here's a good example of that.
Speaker: This is a patient, this is a paper published in The Lancet in 1993, who
Speaker: And what you see is a patient who took an overdose of enalapril, a very well-known ACE inhibitor.
Speaker: And what you see is that despite catecholamines, they cannot maintain their blood pressure until they rescue the patient with angiotensin II.
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.
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,
Speaker: you get catecholamine resistance.
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.
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.
Speaker: And we refer to this construct as the RAS disturbance hypothesis.
Speaker: And essentially, everyone is very familiar with the angiotensinogen renin to age one, ACE converting age one to age two, and then aldosterone.
Speaker: And this is
Speaker: pretty well codified.
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.
Speaker: However, when you get severe shock and endothelial injury, you hit a bottleneck.
Speaker: You're on the highway, six lanes go to two.
Speaker: And when that happens,
Speaker: The things that come before the bottleneck, such as renin and angiotensin 1, increase.
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.
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.
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.
Speaker: So, the brief summary of the phase three registration trial was that it was a test of angiotensin-2 as a vasopressor.
Speaker: The primary efficacy endpoint was MAP.
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.
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.
Speaker: This is not the full inclusion or exclusion criteria.
Speaker: But patients with non-vasodilatory shock were excluded.
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%.
Speaker: And so we were rigorous about these criteria.
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.
Speaker: And, oh, wait a minute, there are CVPs too.
Speaker: Oh, there are CVPs four.
Speaker: You know, and what have you.
Speaker: And they weren't appropriately resuscitated, and those patients did not make the trial.
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.
Speaker: So this is the Kaplan-Meier curve showing you the mortality survival of patients in the ATHOS-3 trial.
Speaker: And you can see a very nice trend line and early separation between the two groups, but this did not achieve statistical significance.
Speaker: Realize and recognize that this trial was not powered to show a survival benefit.
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.
Speaker: Importantly, we set out to understand and determine
Speaker: if the ACE effect was operational and important in the trial.
Speaker: And the way we did this is we measured the angiotensin 1 and angiotensin 2 levels at baseline.
Speaker: And the rationale for this is that we wanted to assess the function of endothelial ACE.
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,
Speaker: and its product, angiotensin II.
Speaker: And we basically made, we surmised that this ratio would help us understand the level of ACE function.
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.
Speaker: Now, this is not the only way that ANG1 becomes ANG2.
Speaker: There are some other mechanisms that do exist, but they don't appear to be very operational in shock.
Speaker: And that, perhaps, is something, Sergio, we can talk about at the end of the talk in the questions.
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.
Speaker: Recognize that the normal value is 0.5.
Speaker: So in shock, the edge one, edge two ratio is quite disordered.
Speaker: And if you are closer to the normal range, you do not see a survival benefit.
Speaker: However, if your ratio is elevated,
Speaker: We demonstrate a statistically significant survival benefit in a pre-specified analysis, which is a really big deal.
Speaker: And we were really pleased to show this result because this was not data dredging at the end.
Speaker: This was an a priori hypothesis.
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.
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
Speaker: norepinephrine is very cheap.
Speaker: The hospital environment is incredibly austere.
Speaker: We really want to use angiotensin 2 when we know we get a survival benefit and not just a MAT benefit.
Speaker: And so when will you provide us the angiotensin 1, angiotensin 2 bedside test that drops into an ISTAT?
Speaker: I think it's the right request, but the answer is this is not going to happen anytime soon.
Speaker: And allow me to take a belief diversion into why this will not happen anytime soon.
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.
Speaker: And that process is, aside from being expensive, takes a lot of time.
Speaker: because you have to develop these assays that are very robust
Speaker: You then have to make them robust that they have very low coefficient of variations.
Speaker: You then have to put it onto a platform.
Speaker: You have to validate that platform.
Speaker: You have to build the platform.
Speaker: And then you have to show in a new study that that exact companion diagnostic maps to the outcome that you said.
Speaker: And I think all of that is well worth doing, but it doesn't happen fast.
Speaker: And so we have sought to find...
Speaker: something that allows the clinician to arrive at this determination sooner because while this process continues, it takes years, many years in fact.
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.
Speaker: And to be honest, I didn't initially look at renin because I was concerned that it may not be very stable.
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.
Speaker: And I was just profoundly delighted to see this paper published by
Speaker: Gleason and colleagues, which is based out of Jacques Couture's and Jean-Louis Vincent's shop in Brussels, Belgium.
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
Speaker: It wasn't affected by diurnal variation.
Speaker: It wasn't affected by other drugs.
Speaker: There are some data that suggest that catecholamines can affect reading levels.
Speaker: They did not see this.
Speaker: And importantly, it's not affected by dialysis.
Speaker: And I think the thing that stunned me is that it outperformed lactate.
Speaker: I'm going to say this again because...
Speaker: This is not obvious.
Speaker: Renin outperformed lactate as a predictor of ICU survival.
Speaker: Which is really quite remarkable.
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.
Speaker: After all, renin is in the RAS system.
Speaker: It is the R in the RAS system.
Speaker: It is the renin-angiotensin-aldosterone system.
Speaker: And so I'll show you some of the data related to this.
Speaker: So the first thing we set out to do is, does the renin correlate with the ratio?
Speaker: So can it be used in place of the ratio?
Speaker: And the answer is yes.
Speaker: The p-value is highly statistically significant.
Speaker: And what you see is a very nice correlation between renin and the ang1-ang2 ratio.
Speaker: So that was a good first step to give us confidence that this might actually be a way in which to guide care.
Speaker: Now, if you look at the patient population, the patients who have a low renin, right?
Speaker: So these are patients who are normal.
Speaker: Their angiotensin-converting enzyme capacity is more normal.
Speaker: There is no survival benefit.
Speaker: What you can see is these two curves are superimposed on one another, and there is no survival benefit.
Speaker: However, if you don't have...
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.
Speaker: The relative risk is 0.55.
Speaker: The difference here in survival is 50% versus around 70%, which is an absolute delta of 20%.
Speaker: That means in the high renin group, the number needed to treat to save one life is five.
Speaker: Single-digit number needed to treat is simply outstanding.
Speaker: And I want you to look at the early separation here.
Speaker: These high renin patients who get placebo die very quickly.
Speaker: By day seven, half are dead.
Speaker: by day seven, half are dead.
Speaker: Right?
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.
Speaker: Of course, as always,
Speaker: The rubber meets the road in the multivariate analysis, and angiotensin II treatment holds up.
Speaker: It remains statistically significant when you adjust for the stratification variables and the variables that were imbalanced in the trial.
Speaker: with a hazard ratio of 0.62, which means it gives you a 38% survival benefit that is statistically significant.
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.
Speaker: Now, I think the thing which really pleased me was that you also saw an enhanced safety profile.
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,
Speaker: They have less high-grade adverse events, which is essentially serious adverse events.
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.
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.
Speaker: That is not what you normally see.
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.
Speaker: So not only do you...
Speaker: use renin to allow you to identify the patients who get a spherol benefit, it allows you to be safer.
Speaker: And that is something which you don't see very much, and we were very happy about this result in this finding.
Speaker: Now, I think there's an important question here, which is that, why does the renin go up?
Speaker: Could it be up for other reasons?
Speaker: I mean, are you missing something?
Speaker: Well,
Speaker: There are other things that make the renin go up.
Speaker: One of them is essential hypertension.
Speaker: The good news here is that everybody was in shock, so hypertension is really not a problem.
Speaker: Malignant hypertension can also raise your renin.
Speaker: Not an issue.
Speaker: These patients are profoundly hypotensive on high-dose vasopressors.
Speaker: Could they be bleeding?
Speaker: Bleeding does increase your renin, but active bleeding was an exclusion criteria in the trial.
Speaker: Cirrhosis can raise your renin, also excluded in the trial, liver failure.
Speaker: I think the most common thing people tend to see is renal vascular hypertension and, of course, exceedingly rare renin-producing tumor.
Speaker: So if you sort of look at this, this is the normal range of the assay, 0 to 50.
Speaker: This is what happens when you have renal artery stenosis.
Speaker: You get yourself up to around 150, maybe 200.
Speaker: This is the range at those three.
Speaker: The median value is 161, which is around three times the upper limit of the normal of the assay.
Speaker: It told you it was 0 to 50, so it was 150.
Speaker: The highest value is up as close to nearly 6,000.
Speaker: So the renins are not slightly elevated.
Speaker: They're unbelievably elevated.
Speaker: And these data match very closely to the range of renin shown in shock by the Gleason data.
Speaker: And so this is not just us and our data saying that the renins are high.
Speaker: This is mapping and matching directly to other data published looking at this exact type of effect.
Speaker: So I think, you know, it's important to think about this
Speaker: Is ace dysfunction, does it behave in the way that we are imagining it that it should?
Speaker: So if there's a block in the road, antitensin-converting enzyme is not working, do these things actually back up?
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?
Speaker: How would I go about trying to understand how to make this assessment?
Speaker: So the simplest way to do it is to give an ACE inhibitor.
Speaker: So an ACE inhibitor is an incredibly controlled way in which to assess the
Speaker: the effect of angiotensin-converting enzyme dysfunction because you induce it with the drug.
Speaker: And if you give an allopril, this should not surprise anyone, the blood pressure goes down.
Speaker: Well, not only that, the renin goes up.
Speaker: So you give an allopril, blood pressure goes down.
Speaker: Renin goes up.
Speaker: That makes sense.
Speaker: Okay.
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.
Speaker: And they used Captopril, which back then was a squib molecule, squib 14-225.
Speaker: And what they did is they took healthy volunteers and they gave them Captopril.
Speaker: And what you can see over a two-hour period of time, which I think in my mind is quite dynamic,
Speaker: you see nearly a doubling of the renin in two hours.
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?
Speaker: So, adjutensin-converting enzyme is not working.
Speaker: It's pulled down by enalopril.
Speaker: There is a
Speaker: narrowing of the freeway, you're going from six lanes to two, and the renin and angiotensin one back up.
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.
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.
Speaker: And they actually did this in 1979.
Speaker: And what you see quite beautifully is when you give angiotensin 2 to someone who has had a deliberate
Speaker: embarrassment of adjutensin-converting enzyme function is there is biofeedback and the renin goes down.
Speaker: The engagement of the ATR1 receptor with adjutensin 2 causes an appropriate biofeedback response of renin reduction.
Speaker: And so we set out to sort of characterize this, and we published these data in 2018 in critical care.
Speaker: And essentially, what we're saying is this.
Speaker: You get endothelial injury, typically from septic shock.
Speaker: But as anyone who's listening to this WebEx knows, it can be from a variety of different things.
Speaker: And if that happens, you get less effective ATR1 receptor engagement because there's not enough angiotensin to around other things.
Speaker: This then causes an increase in renin.
Speaker: which causes the body to increase the production of angiotensin 1.
Speaker: Now, if you then bring angiotensin 2 exogenously into this environment, you engage the ATR1 receptor, this then sets off appropriate biofeedback.
Speaker: This is demonstrated in healthy volunteers who have deliberate ACE inhibition, ACE dysfunction initiated.
Speaker: This is also shown in preclinical models.
Speaker: the renin goes down, which should cause the angiotensin I levels to go down.
Speaker: So if the RAS disturbance hypothesis is operative in shock patients, what you ought to see
Speaker: is a reduction in renin and angiotensin 1 with the introduction of angiotensin 2 into that environment.
Speaker: And that is exactly what we see.
Speaker: So here are the patient's angiotensin 1 levels.
Speaker: In placebos in red, you can see it's quite flat.
Speaker: The change is around 8.5%.
Speaker: This is baseline.
Speaker: And now you have either drug or placebo.
Speaker: And then hour 3 later.
Speaker: And what you can see...
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.
Speaker: And the renin follows directly in suit, in lockstep, as anticipated,
Speaker: you'd expect to see if you have significant ACE dysfunction.
Speaker: In the placebo arm, you can see it's very flat.
Speaker: And here, with those folks who get angiotensin II, you get a marked reduction, a 50% reduction in just three hours.
Speaker: And obviously, both of these findings are highly statistically significant.
Speaker: And so remember that all these placebo patients, right, they're all well-resuscitated.
Speaker: Okay?
Speaker: They're all on catecholamines.
Speaker: And 70% of them are vasopressin.
Speaker: So this inability to decrease your renin and angiotensin 1, respectively, is not because they have a catecholamine, vasopressin, or crystalloid defect.
Speaker: This is about the difference between getting angiotensin 2 versus placebo.
Speaker: Now,
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.
Speaker: He said, you know, Mink, the angiotensin 1 level is dropping so massively.
Speaker: It's really striking.
Speaker: He said, could some of the benefit that we're seeing be because the angiotensin 1 level goes down?
Speaker: Is angiotensin 1 bad for you?
Speaker: And that's a pretty good question.
Speaker: And, you know, it turns out that he was right.
Speaker: And I'll show you why.
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.
Speaker: And we've already been through this once in this talk, and many of you know this already.
Speaker: But there's also...
Speaker: a non-classical pathway of angiotensin metabolism.
Speaker: And this pathway is in contradistinction to the classical pathway, which is vasoconstrictive.
Speaker: This pathway is the opposite.
Speaker: It's vasodilatory.
Speaker: And what happens is if there is ACE dysfunction, you then can have angiotensin 1 being metabolized to angiotensin 2 to 7,
Speaker: and 1 to 7.
Speaker: And if there's an ACE defect, this can then cascade, right?
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.
Speaker: It gets shunted in 2 to 7 and 1 to 7.
Speaker: And we also know that bradykinin levels are elevated in shock, and that's important because bradykinin is also a profound vasodilator.
Speaker: And so...
Speaker: What we think is happening is that this non-classical pathway is becoming much more operational.
Speaker: Now, many of you have not heard of these other angiotensins, 2 to 7, 1 to 7, and whatnot.
Speaker: And I just want to show you some data to show you that these data are really well-sorted already.
Speaker: This has been worked out.
Speaker: These are data published in 1996, and these are patients who are being initiated on Captopril for hypertension.
Speaker: And what they find is that your angiotensin 1 to 7 levels
Speaker: are the key to gaining a hypotensive, a decrease in your high blood pressure.
Speaker: This is a graph showing you the diastolic blood pressure plotted against the plasma angiose 1 to 7 level.
Speaker: And what you can see is the more your angiose 1 to 7 level goes up, the more your blood pressure goes down.
Speaker: Anginism 1 to 7 is a highly effective vasodilator.
Speaker: It's such an effective vasodilator that it's being worked on by other drug companies as an antihypertensive.
Speaker: And, you know, I think this paper that recently came out, I think, really shows this beautifully.
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.
Speaker: And what you see here is GFR is over here on the y-axis.
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.
Speaker: But if you are hyperfiltering from induced diabetes, there's this big drop in GFR.
Speaker: But I think more importantly, and this may be more operational for the renal geeks who are listening to this,
Speaker: Look at the change in filtration fraction.
Speaker: This is the effect of the intraglomerular pressure assessment.
Speaker: Angiotensin 1 to 7 functions as the polar opposite of angiotensin 2.
Speaker: Angiotensin 2 increases filtration fraction.
Speaker: Angiotensin 1 to 7, which is one amino acid different, has the exact opposite effect.
Speaker: In essence, angiotensin 1 to 7 is the opposite of angiotensin 2.
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
Speaker: important intrarenal GFR filtration fraction effects.
Speaker: Let me show you some longitudinal data to try and put this into some context.
Speaker: So this is a group of patients, this is from maternal hypertension, 1996.
Speaker: And what you see here are angiotensin I and angiotensin II levels in patients who are naive to captopril.
Speaker: So this is the initial dose of captopril baseline.
Speaker: They have not received their captopril yet.
Speaker: And what you can see
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.
Speaker: So now, you get your capitol dose.
Speaker: You've received an ACE inhibitor.
Speaker: What happens to your angiotensin 2 level?
Speaker: It doesn't go down.
Speaker: But your angiotensin 1 level goes way up.
Speaker: Now, it's six months later.
Speaker: You've been on capitol three times a day.
Speaker: This is your pre-dose.
Speaker: And what you can see is that your pre-dose looks very similar to your post-dose back over here.
Speaker: Notice the angiotensin II level is not lower than the first day that they started.
Speaker: Now you get your catapryl dose and you look at your post-dose.
Speaker: The angiotensin II level has not gone down.
Speaker: But your angiotensin I level has gone way up.
Speaker: And this has been shown in many other studies.
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.
Speaker: ACE inhibitors don't cause dramatic drops in angiotensin II.
Speaker: ACE inhibitors do not cause dramatic drops in angiotensin II.
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.
Speaker: This is from the heart failure literature and the hypertension literature.
Speaker: I have not shown you any shock data yet when it comes to this.
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.
Speaker: You take these patients who have significant angiotensin-converting enzyme dysfunction,
Speaker: you give them angiotensin 2 back, and it initiates a process of biofeedback.
Speaker: Now, I've already shown you the renin goes down and the angiotensin 1 goes down.
Speaker: When that happens, you get less vasodilatory non-classical pathway angiotensins.
Speaker: You remove angiotensin.
Speaker: bad-acting vasodilators.
Speaker: These vasodilators, if you have heart failure, if you have hypertension, are glorious and wonderful.
Speaker: If you are in shock, not so bueno.
Speaker: Because these are ACE metabolites, it's likely, and this is now supposition, that this ACE availability likely increases, which also decreases bradykinin.
Speaker: Now, this is sort of a lot to take in, and this is sort of like too many boxes with too many colors.
Speaker: If you remember nothing else from this WebEx, this is the slide that you should recall.
Speaker: Basically, what I am saying is that when you have an angiotensin-converting enzyme defect, it causes an imbalance.
Speaker: And this imbalance favors vasodilation.
Speaker: with increases of angioma-1-7, bradykinin, and other non-classical angiotensins, which I refer to as angiotensin detritus.
Speaker: ACE impacts not just macro, but micro-hemodynamic alterations.
Speaker: And we believe that the
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.
Speaker: Because essentially, you have a dual defect when you have angiotensin-converting enzyme dysfunction.
Speaker: Importantly...
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.
Speaker: Now, allow me to sort of take you back to some basic
Speaker: renal physiology.
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.
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.
Speaker: In an inhibited and dysfunctional state,
Speaker: The efferent arterial is vasodilated.
Speaker: This decreases the intraglomerular pressure, which causes less ultrafiltrate.
Speaker: When you restore angiotensin to effect... And now, remember, this is not just...
Speaker: by giving angiotensin 2, it's by reducing angiotensin 1 to 7 as well, because the net effect is all of that.
Speaker: You restore intraglyneural pressure when you get efferent tone back, and this improves filtration and ultrafiltrate.
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
Speaker: The most severe ones are the ones who ought to benefit.
Speaker: And that's exactly what we show.
Speaker: This is data published in Critical Care Medicine 2018.
Speaker: I want you to look at this.
Speaker: The median renin level in the AKI patients is 352.
Speaker: The median for the overall population is 161.
Speaker: Right?
Speaker: So what this means...
Speaker: is patients with AKI have a more severe ACE disturbance, as you'd expect.
Speaker: High renin means low effective angiotensin II and low GFR.
Speaker: When you give angiotensin II to these patients, you see a really dramatic survival benefit.
Speaker: The p-value is highly statistically significant, 0.01.
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.
Speaker: But I think the most important thing is not just a survival benefit.
Speaker: And you can say, geez, mate, what's more important than survival?
Speaker: I will tell you as a nephrologist,
Speaker: getting off of dialysis is really important.
Speaker: And this is exactly what we show.
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.
Speaker: Now, you know...
Speaker: I recognize that bringing in a new drug is expensive.
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.
Speaker: And if you don't ever get them fixed and they do manage to survive, they become an ESRD patient.
Speaker: angiotensin II, more rapid renal recovery.
Speaker: What are you doing for AKI now, aside from more dialysis?
Speaker: And we mechanistically link this.
Speaker: And just so you understand what I'm trying to say here, I want to just spend a moment differentiating two key concepts.
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.
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.
Speaker: That's a biotype.
Speaker: It's a biologic assessment of the subform of disease that you have.
Speaker: So we know now that high renin and low renin are biotypes of vasodilatory shock.
Speaker: Having ARDS or acute kidney injury requiring renal replacement therapy, that's your clinical phenotype.
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.
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?
Speaker: It's a patient with severe acute kidney injury.
Speaker: It's just that simple.
Speaker: Now, it's not perfect, but it's pretty good.
Speaker: 75% to 85% of the time, you're going to be able to localize that high renin group just on that clinical phenotype.
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
Speaker: of a razor presser to improve an outcome.
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.
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.
Speaker: And high renin, I think for purposes of this localization of biotype, is three times the upper limit of normal.
Speaker: So, if you're labbed, the upper limit of normal is 40, it's 120.
Speaker: In our trial, the renin assay we used, the upper limit of normal was 50.
Speaker: And so, we used a median cutoff.
Speaker: So, 150 is very close to the medians.
Speaker: And we've done a sensitivity analysis looking at this.
Speaker: And it's not just the median happens to be so simplistic.
Speaker: It happens to be where you get the most...
Speaker: benefit lined up when you look at it through different cutoffs as well.
Speaker: I didn't show you those data in the interest of time, but I think it's important for you to know that.
Speaker: Most importantly, if you now take this group, right?
Speaker: So if you take acute kidney injury or RT, I showed you this data.
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.
Speaker: The recovery
Speaker: the liberation from RRT improves from an odds ratio of 2s to 4.
Speaker: And it's highly significant.
Speaker: And the separation between the recovery group and the non-recovery group is even wider.
Speaker: So the biotype actually informs onto the clinical phenotype, which suggests, at least to me, that the biotype is more important.
Speaker: Now, you know, I know this has been a lot of information that I've kind of thrown down here.
Speaker: So, you know, hopefully you'll have an opportunity to sort of let some of this sink in.
Speaker: But I want to put this back into some basic context.
Speaker: In general, I'm loathe to quote Don Rumsfeld, but, you know, here you are.
Speaker: These are known known.
Speaker: So let me just take you through known knowns, things which we know to be true.
Speaker: Endothelial injury is a hallmark of septic shock.
Speaker: I don't think this is a controversial statement.
Speaker: In fact, in some instances, this is part of the definition of septic shock.
Speaker: This is also well-established.
Speaker: Angiotensin-converting enzyme is an endothelial membrane-bound enzyme.
Speaker: If you don't believe me, please look it up in a textbook or in the literature.
Speaker: Sadly, too many of you will go to the Google and find it on Wikipedia, but I guess that's acceptable.
Speaker: But ACE is an endothelial membrane-bound enzyme.
Speaker: Excuse me.
Speaker: ACE dysfunction in septic shock is not a new finding.
Speaker: I didn't show you this in the interest of time, but this is not new.
Speaker: Many investigators in both preclinical and human data have demonstrated that when you get septic shock, you get ACE dysfunction.
Speaker: The elevated renin piece...
Speaker: is been shown by various investigators previously.
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.
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.
Speaker: All that I think that we're saying here in this synthesis is all of this is happening in vasodilatory shock as well.
Speaker: It may not be 2 plus 2 is 4.
Speaker: I think it's more that 2 plus 2 plus 2 plus 2 plus 2 plus 2 is 12.
Speaker: None of what I have shown you
Speaker: is something that is a brand new concept that has never been put together any meaningful way.
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.
Speaker: Now, I don't think many of you believe me.
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.
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.
Speaker: And that's, you know, in really simplistic terms, the case.
Speaker: And it can't be that simple or it can't be that obvious, whatever it can't be or shouldn't be.
Speaker: I know that people don't believe this is the way that it is.
Speaker: So here's what I suggest you do.
Speaker: I suggest you start measuring renin by yourself.
Speaker: It's a $5 test.
Speaker: A 96-well ELISA go online for renin.
Speaker: 96 wells is around $350.
Speaker: That's less than $5.00.
Speaker: The test.
Speaker: When you have a patient and they're in shock and they have acute kidney injury, measure a renin level.
Speaker: You tell me if it's elevated.
Speaker: Then give whatever goofy intervention you want to give.
Speaker: You want to give more crystalloid and try and create another saltwater drowning in a modern ICU?
Speaker: Knock yourself out.
Speaker: You want to give another catecholamine?
Speaker: Right?
Speaker: They're already on like 100 of norepi.
Speaker: You're going to add epi to find that alpha receptor that's a witness protection in the amygdala?
Speaker: Knock yourself out.
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.
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.
Speaker: And then tell me what happens to the renin levels.
Speaker: Is any of this voodoo working?
Speaker: Is any of this voodoo helping you get the patient better?
Speaker: You don't need to believe anything that I've shown you.
Speaker: Angiotensin 2 is an approved drug in the United States of America and Europe.
Speaker: Renin is a cheap, accessible test.
Speaker: Do it for yourself.
Speaker: Tell me if this is real or not.
Speaker: You can come back to us and say, yeah, you guys are full of it.
Speaker: Let's see if this holds up.
Speaker: And when you do measure the renin, and if it comes back high, this is my exclusive request.
Speaker: Ask yourself, why is it so high?
Speaker: Is it because you didn't give them enough saline?
Speaker: You didn't waterboard them enough?
Speaker: Is it because they're not on enough catecholamine?
Speaker: They're not on enough antibiotic?
Speaker: Why is the renin so high?
Speaker: Or might it be because
Speaker: of an angiotensin-converting enzyme defect due to anethyl dysfunction.
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?
Speaker: Ask yourself, did you do everything that you possibly could have for that patient?
Speaker: Because I would argue that in a high-renin shock patient, they deserve a prompt intervention that deals in the RAS system.
Speaker: That is the only, in my view, reasonable conclusion that one can arrive at.
Speaker: And I'll show you a recent case to try and illustrate this.
Speaker: This is provided to me from a friend of mine named John Chow.
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.
Speaker: They ended up crowing out Morganella and Morgani in the patient.
Speaker: And despite the methylene blue hydroxycobalamin,
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.
Speaker: This patient was on vasopressors for five weeks.
Speaker: Five weeks, the patient was in shock.
Speaker: And John decided to check a renin level.
Speaker: And he checked a PRA, which was all they really had, which I think is okay.
Speaker: I think a direct renin level is better, but, you know, not one to complain here.
Speaker: And it was 53.
Speaker: The upper lip of normal is 2.
Speaker: That's 25 times the upper lip of normal.
Speaker: It's pretty high.
Speaker: he managed to acquire angiotensin II for the patient, and I'll show you the results.
Speaker: So this is the patient in question.
Speaker: They've been in shock now.
Speaker: So this is the vasopressin dose here.
Speaker: This is the norepinephrine dose here, up as high as 0.8.
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.
Speaker: So now the patient gets angiotensin II with 20 nanograms per gage per minute.
Speaker: The patient becomes immediately hypertensive.
Speaker: The norepinephrine dose and vasopressin dose go to zero, to zero in four minutes.
Speaker: Been in shock for five weeks, off norepinephrine and vasopressin in four minutes.
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.
Speaker: There's about 10.
Speaker: And this is what happens to the PRA.
Speaker: It starts at 53.
Speaker: In three hours, it drops by over 50%, identical to the ATHOS-3 data, which is a little bit more than 50%.
Speaker: Within 24 hours is under 10.
Speaker: The upper level of normal for the PRA is 2, so pretty close to normal and stays suppressed.
Speaker: Within 48 hours, the patient who had been on TPN was now tolerating PO.
Speaker: The patient who had been on CRT and they couldn't take volume off, they were able to get the patient negative.
Speaker: and were able to switch to intermittent hemo.
Speaker: And within three days, after being in the ICU for five weeks in shock, went to the floor off of all vasopressors.
Speaker: What if they had just let this guy be in shock with vasopressin and norepinephrine for another five weeks?
Speaker: So in my view, there's more than just the clinical opportunity to make someone better, which I think is obviously hugely important.
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.
Speaker: I think there's an opportunity to bring these people back.
Speaker: And let me explain what I mean in a little more clarity.
Speaker: It's my view that many of the old drugs, in fact, work.
Speaker: I was a fan of activated protein C. I think activated protein C worked.
Speaker: I think that other drugs have a capacity to work.
Speaker: And I think that these high renin vasoplegic patients may be part of the reason why we don't get consistent results.
Speaker: And let me walk you through some of my thinking.
Speaker: So imagine you're running a large randomized control trial.
Speaker: You have an active arm, and you randomize them to protein C, early gold rectotherapy, alkaline phosphatase, steroids, whatever.
Speaker: Within both arms of your septic shock trial, you are going to get a bunch of high renin shock patients.
Speaker: They may or may not be balanced.
Speaker: You may get unlucky, and they get imbalanced.
Speaker: The problem is, is these people dampen your effect.
Speaker: These folks don't get better.
Speaker: They have a very high mortality.
Speaker: They have high levels of endothelial dysfunction, which we measured and looked at.
Speaker: I didn't have time to show you those data.
Speaker: And they become catecholamine-resistant.
Speaker: So they just die.
Speaker: Well, if you then say to yourself, well, this dampening of the signal by hyarine and shock
Speaker: Well, how can you figure that out?
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.
Speaker: And in the low renin arm, I'll bet you a lot of these interventions work.
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.
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.
Speaker: So in conclusion, we confirm that
Speaker: that elevated renin shock is associated with a worse survival and severe AKI.
Speaker: And I want to make this very clear.
Speaker: This is a confirmation because elevated renin and outcomes has been in the literature since 1983.
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.
Speaker: Elevated renin shock is a biotype for shock, and it's also an AKI biotype.
Speaker: Angiotensin II infusion effectively suppresses both renin and angiolone.
Speaker: This strongly suggests that the angiotensin-converting enzyme defect is driving this effect.
Speaker: And the insufficient ATR1 receptor engagement is the reason for the high renin in the first place, because nothing else pushes it down.
Speaker: And the Gleason data show that renin is a better predictor of ICU survival than lactate.
Speaker: And now you have an agent that allows you to bring that down.
Speaker: And we have shown you that that identifies patients who gain survival benefit.
Speaker: This biotype improves outcomes in elevated renin shock, AKI.
Speaker: We also did it in ARDS.
Speaker: So, elevated renin is an ARDS biotype as well.
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.
Speaker: And serum renin is inexpensive.
Speaker: It's widely available.
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.
Speaker: And my prediction is,
Speaker: that within two years, serum renin will replace FINA in patients with shock and AKI.
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.
Speaker: But that is a rant for another time.
Speaker: And with that, for those of you who've hung in here for the duration of this talk, I'll move to questions.
Speaker: And I would like to thank Sergio again for the opportunity to share with you guys some new data.
Speaker: And hopefully, these data will be published in the very near future.
Speaker: Thank you.
Speaker: Excellent.
Speaker: So we've concluded with the video.
Speaker: I know that we've had some technical difficulties, but I did get some questions.
Speaker: text it to me, Mink, and I think that we can go ahead and maybe entertain some of those.
Speaker: And first, I think that thanks for sharing all this new data with us.
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.
Speaker: But I would like to start, Mink, if it's okay, with some physiopath questions
Speaker: that I think are of interest.
Speaker: And you did talk about the biotype versus the clinical phenotype.
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?
Speaker: Yeah, so that's a great question.
Speaker: And, you know, I think that
Speaker: The answer is from the ATHOS data alone, I don't think we can say with 100% certainty which one it is.
Speaker: But in my view, it's almost certainly a biotype, not just severity of illness.
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.
Speaker: in mortality and its improvement in survival despite those features.
Speaker: And so it's my suspicion that certain patients develop a more severe endothelial type of injury.
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.
Speaker: I think all these things contribute.
Speaker: And then I think my view, probably what happens is
Speaker: you hit a critical point of endothelial injury where your body paints itself into this corner.
Speaker: So it's vigorously trying to make more and more angiotensin 1 by increasing the renin.
Speaker: And that angiotensin 1, instead of going to angiotensin 2, gets shunted into this vasodilatory pathway, and it just makes everything worse.
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
Speaker: The first ACE inhibitor was discovered in the venom of a Brazilian pit viper.
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.
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.
Speaker: But,
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.
Speaker: And so I think that this is something which the body does not prepare itself well for.
Speaker: And when you hit that critical threshold of an endothelial injury, you get trapped into this vasoplegic, you know, ACE defect corner.
Speaker: Are there patients that, you talked about the clinical phenotype of the high renin.
Speaker: Are there patients who have normal renin that still need dialysis?
Speaker: And in those patients, do we know, I mean, the effect of Agitensin II?
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.
Speaker: And so AKI alone,
Speaker: isn't enough because the benefit is in the high renin patients.
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.
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.
Speaker: So in a perfect world,
Speaker: you would use as of now the renin level as a better discerner of who an agitantism to might be helpful.
Speaker: Yes.
Speaker: And so I think the issue, yeah, that's right.
Speaker: So the issue now is that most hospitals in the country, the turnaround time is it's send out.
Speaker: And I think that a lot of hospitals can get it back within 36 hours.
Speaker: And so I think it's very similar to the blood culture.
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.
Speaker: And if it's below three times your blue abnormal, you deescalate.
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.
Speaker: I think that's the future.
Speaker: We wrote a paper
Speaker: that came out about six months ago called broad spectrum vasopressors.
Speaker: Ironically, at the time, we didn't have the renin data, otherwise I would have put it in that paper.
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.
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
Speaker: and start broad-spectrum beta suppressors and then de-escalate this appropriate.
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.
Speaker: People have ordered it.
Speaker: So this is something that clearly you have mentioned.
Speaker: It's not an expensive test.
Speaker: It's not maybe something that has a rapid turnover and hospitals can get it.
Speaker: Is the range usually within the similar ranges or the different assays that people use and we should just use the 3X?
Speaker: Can you give us a little bit more
Speaker: of the practical aspect of it, Mink?
Speaker: Yeah, that's a good question.
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.
Speaker: If you look at the plasma range, the range is like 2.5 to 25.
Speaker: Of course, the assay differs.
Speaker: I think the easiest thing to do is to take the upper limit of normal and do 3x the upper limit of normal.
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.
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.
Speaker: So for instance, take any direct assay you have.
Speaker: Let's say your lab runs assay 42, whatever that is.
Speaker: And the assay in your lab comes back and the normal range is 10 to 60.
Speaker: Well, that means that if the patient has a value above 180, that's someone who
Speaker: is going to get a survival benefit from angiotensin too.
Speaker: Because even though these assays don't have the exact same normals, they all scale very similarly.
Speaker: Okay.
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.
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.
Speaker: And there'll be a very fast blood culture, which I think would be great.
Speaker: And that would be a phenomenal place to be.
Speaker: I mean, I think for smaller hospitals that don't have it, waiting two days is maybe too long.
Speaker: I think it's not terrible.
Speaker: Five days is too long.
Speaker: So I think clinicians are going to say, look, if it is a sundown, we get it.
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.
Speaker: I think similarly waiting for your vasopressor sensitivity assessment for five days is too long.
Speaker: So I think getting it within 48 hours is minimum.
Speaker: I think within 24 to 48 is ideal.
Speaker: Okay.
Speaker: So let me ask you a bedside question, and then I would like to move maybe into more of hospital bedside.
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?
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.
Speaker: I think most people would agree that norepinephrine would be the first line.
Speaker: If I'm escalating that or not getting the MAP that I want, I would add a second drug.
Speaker: Perhaps if somebody had renal failure, that would be angiotensin 2 or in many places might be vasopressin.
Speaker: But very quickly thereafter, I would be adding a third drug if the patient was not doing well.
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
Speaker: adding more catecholamines.
Speaker: So obviously angiotensin II would be the obvious next phase.
Speaker: And at that point, you would be sending hopefully a renin test and treating the patient.
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
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?
Speaker: Is that the way you would approach it at the bedside, Ming?
Speaker: Yeah, I think that's exactly right.
Speaker: And I think that the important thing to remember is there is also this notion of
Speaker: excuse me, of the order, whether it's catecholamine first, then ANG2, or catecholamine, then vasopressin.
Speaker: Much of that is driven by habit.
Speaker: But I think the other big question is how sick is the patient, right?
Speaker: And you get a feel for that in an ICU physician.
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.
Speaker: But there are patients that are clearly evolving rapidly in front of you.
Speaker: And in those patients,
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.
Speaker: That to me is insanity.
Speaker: That's like trying to decrease your TPA bill by only giving TPA for stroke after three hours.
Speaker: I mean, this kind of behavior I find profoundly offensive.
Speaker: And then you end up using whatever the drug is, in this case, it's antigenotensin too, late.
Speaker: And people say, oh, it didn't work.
Speaker: I mean, so just so we're clear, it doesn't work in dead people.
Speaker: The trade name is Geopressa, not Liquid Jesus, right?
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.
Speaker: It doesn't mean you're first line, but it means you're extremely prompt.
Speaker: I think checking a REAN level is how you demonstrate value.
Speaker: And you can say, look, this is a survival benefit, but more than that,
Speaker: You know, CRRT costs $4,000 a day all in.
Speaker: Intermittent hemo is like $1,500 a day.
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.
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.
Speaker: But you save the entire healthcare system huge dollars, right?
Speaker: And the hospitals get a save
Speaker: without dialysis, which saves them money.
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.
Speaker: So we ran at those with the idea that we're gonna do a MAP study.
Speaker: And everyone's like, oh, it's MAP, it's MAP, what does MAP mean?
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.
Speaker: And I think clinicians have been asking us, do you have something simple and easy to do?
Speaker: And the answer now is yes.
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.
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.
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 or you already had new and the paper has been published of that benefit in the particular subgroup of renal failure patients, right?
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?
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.
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.
Speaker: So obviously you want to start these therapies early, like you said, not when the patient's dead.
Speaker: But in terms of timing, if the patient's on RRT, you still should start it.
Speaker: I mean, it's not like, oh, they're on RRT, now there's no point, right?
Speaker: Because you might get them off the RRT if I understood the data correctly quicker.
Speaker: Yeah, so that's exactly right.
Speaker: And I will tell you that, you know, this has been one of the biggest surprises of my career.
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.
Speaker: You have to use the AKI biomarkers.
Speaker: I did a lot of work on the Nefrocheck biomarker with John Kellum, and we're telling everyone early, early, early for AKI.
Speaker: And so
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.
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.
Speaker: If they have AKI and they're on dialysis, that is the patient you need to get in on.
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?
Speaker: I mean, it's stunning to me that people think that you can wait so long and cells come back.
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.
Speaker: And you can fix that quickly.
Speaker: And those hydraulics come back quite quickly.
Speaker: And if you look at the curves that I showed you in the talk,
Speaker: you see the separation between recovery happens very quickly.
Speaker: The curves begin to separate within one day.
Speaker: So there's a handful of patients who respond almost immediately.
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.
Speaker: Yeah.
Speaker: And I think that early, obviously, is always better, but rather...
Speaker: late than never as that data you showed us of the poor patient who was in shock for 35 days, right?
Speaker: So there's always opportunity to act and I think it's just kind of- That was incredible.
Speaker: Yeah.
Speaker: Yeah.
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.
Speaker: I thought he was joking.
Speaker: I mean, I've never taken care of a patient who survived 30 days in shock.
Speaker: I mean, 10 days is like a lot.
Speaker: But, you know, I shall be honest with you.
Speaker: Like Jonathan, who's at the University of Maryland, is this super talented, bright guy.
Speaker: I didn't believe him.
Speaker: I didn't believe him until he showed me the slides that I shared with you guys.
Speaker: And I was like, he is not lying.
Speaker: This person has been on Norepi for 13 plus.
Speaker: I mean, I was stunned.
Speaker: And then the fact that he went off all of it in three minutes was like, that is pretty dramatic.
Speaker: But that's the exception, not the rule.
Speaker: I don't want your...
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.
Speaker: Yeah.
Speaker: So that would be a bad approach.
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.
Speaker: These are not necessarily new
Speaker: new discoveries, but it's all putting it together in a different context that makes it so interesting.
Speaker: And it's almost like the puzzle.
Speaker: You keep adding pieces and now you can see the picture, which I think is pretty cool and pretty encouraging.
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.
Speaker: And in the current environment,
Speaker: it's a lot harder to get new drugs on board, especially when there's a cost concern.
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?
Speaker: Yeah, so I think that's a great question.
Speaker: I'll tell you what we did at GW when I was there.
Speaker: And it's that at the end of the day, it's going to be about cost for the hospital.
Speaker: They're terrified about new drugs and expenses.
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.
Speaker: It's not CAR T therapy, which is 500 grand therapy.
Speaker: This is $1,500 a day.
Speaker: It's a course therapy is $3,000 roughly.
Speaker: It's cheaper for a lot of hospitals in the country.
Speaker: And the way you make the conversations, you say, look, we use a lot of vasopressin that doesn't work.
Speaker: Half the time you get vasopressin, there's no blood pressure effect.
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.
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.
Speaker: for which nothing else works.
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.
Speaker: More norepinephrine is not gonna fix it.
Speaker: And this take home point here is that this vasopressor is more than MAP.
Speaker: Getting MAP with norepinephrine to 65 or 70 versus getting a MAP of 65 or 70 with ANCH2 is not the same
Speaker: in a high reading patient, because in a high reading patient, you're addressing their defect.
Speaker: Arguably with norepinephrine, you're making it worse because it causes pre-capillary sphincter basic constriction and exacerbates endothelial injury.
Speaker: So you may make yourself feel better by looking at the macro-human dynamics get better.
Speaker: But as you're doing that and trying to make yourself feel better, keep your hand on the patient's toe.
Speaker: As your big toe becomes white and cold, you can ask yourself if you're doing this patient a favor or not.
Speaker: Fundamentally, I think if you understand physiology, you have to have this available.
Speaker: Now, I think in order to convince your pharmacist, you have to be responsible about it.
Speaker: You can't give it to dead people and you have to find a way to make room for it in the budget.
Speaker: And this is done.
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,
Speaker: and everything else they need to do, they've kind of lost their will to fight.
Speaker: And they'll go in and ask the pharmacist and say, I really need it.
Speaker: The pharmacist says, no.
Speaker: And they just say, okay.
Speaker: And they roll over.
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.
Speaker: I want you to start measuring renin levels in your shock patients.
Speaker: I want you to see what these numbers are.
Speaker: And then you decide if you decide that it's worth the fight to have this for your patients or not.
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.
Speaker: Most patients in shock probably have high catecholamines.
Speaker: That's the whole point, right?
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.
Speaker: I think that's right.
Speaker: And I also think that if you recognize that low-dose catecholamines really help you in shock.
Speaker: When you start getting the high-dose catecholamines, you're getting the toxicity.
Speaker: And no one treats hypertension.
Speaker: If you fail 100 milligrams of BID of metoprolol, no one puts you on a gram of metoprolol.
Speaker: Even though that will bring your blood pressure down.
Speaker: It'll make your heart rate two, but your blood pressure will be better.
Speaker: So we don't do that because it's profoundly anti-intellectual.
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.
Speaker: Yeah, absolutely.
Speaker: So we have another question from the audience regarding any experience or data you could share with us in CKD patients.
Speaker: Yeah, so we did not break out CKD separately in the adathose 3 trial.
Speaker: And a lot of this is because we did not have access to baseline creatinins.
Speaker: It's my suspicion that not just CKD, but what happened to you with your CKD is going to matter.
Speaker: Lots of CKD patients are ACE inhibitors.
Speaker: ACE inhibitors have very long half-lives.
Speaker: Most people don't know this, but ACE inhibitors are pro-drugs.
Speaker: So they have half-lives at 50 hours or so.
Speaker: So if they were taking an ACE inhibitor,
Speaker: and then they got sick, or an A2 blocker, and then they got sick, that drug is still in their system.
Speaker: And so A2 helps ameliorate both patients on ACE inhibitors and A2 blockers, although the A2 blocker part's a little bit counterintuitive.
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.
Speaker: And there's the background that CKD patients tend to have more ACE expression on their endothelium.
Speaker: And so how that translates in a shock state, we just don't know at this point.
Speaker: And I think one of the things which is exciting with this discovery, frankly, is there's so much left to learn, right?
Speaker: This is just the beginning.
Speaker: This is okay.
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.
Speaker: Absolutely.
Speaker: I think that,
Speaker: These are very fascinating developments.
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.
Speaker: I mean, you really have been so gracious with your time and expertise.
Speaker: I think that you can either read all the articles on ang2
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.
Speaker: Any parting thoughts for the audience, Mink?
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.
Speaker: And what I would say is that, you know,
Speaker: One of the things that you guys do as a group is you go into hospitals to create value.
Speaker: And it's not just cost containment value and giving better care.
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.
Speaker: That is a huge opportunity.
Speaker: And I would love to see your group
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.
Speaker: Absolutely.
Speaker: And the last thing I want to thank you is for reminding me of my pharmacology days
Speaker: of reading about ACE inhibition and Goodman and Gilman, and now knowing that I wasted all my time in that very long chapter.
Speaker: It was all wrong.
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.
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%.
Speaker: So I think you've probably had a very similar experience in your career, and it remains humbling.
Speaker: But yes, everything you learned about how an ACE inhibitor works is actually wrong.
Speaker: Ming, thank you so much for your time again.
Speaker: This was a great, great conversation.
Speaker: Thanks, Sergio.
Speaker: Take care and go Eagles.
Speaker: Thank you.
Speaker: Thank you for listening to Critical Matters, a sound critical care podcast.
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Speaker: Sound Critical Care is transforming the way critical care is provided in hospitals across the country.
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