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: And now, your host, Dr. Sergio Zanotti.
Speaker: Welcome to another episode of Critical Matters.
Speaker: In our first episode of the podcast, we discussed the potential role of Agitensin-2 in the treatment of distributive shock based on the results of the ATHOS III clinical trial.
Speaker: Now angiotensin 2 is FDA approved and commercially available as a product named Gypressa.
Speaker: In this episode, we will discuss this topic further.
Speaker: It's a great pleasure to have as our guest, Dr. Lakmir Chawla.
Speaker: Dr. Lakmir Chawla is Chief Medical Officer at La Jolla Pharmaceutical Company in San Diego.
Speaker: Previously, Dr. Chawla was a Professor of Medicine at the George Washington University, where he had dual appointments in the Department of Anesthesiology and Critical Care Medicine and the Department of Medicine, the Division of Renal Disease and Hypertension.
Speaker: Dr. Chawla was also the Chief of the Division of Intensive Care Medicine at the Washington, D.C.
Speaker: Veterans Affairs Medical Center.
Speaker: During his tenure at George Washington, Dr. Chawla was a designer and lead investigator of the ATHOS study, which was the angiotensin II for the treatment of high output shock trial, which results led to the phase III trial, ATHOS III, and the eventual approval of this new therapy.
Speaker: Dr. Chawla is an internationally renowned expert and investigator in the field of acute kidney injury, shock, continuous renal replacement therapy, dialysis, and abdomen dialysis.
Speaker: Dr. Chawla is also the author of over 100 peer-reviewed publications and was previously an associate editor of the Clinical Journal of the American Society of Nephrology.
Speaker: Mink, it's a real pleasure to have you on Critical Matters.
Speaker: Welcome.
Speaker: Thank you very much, Sergei.
Speaker: Delighted to be here.
Speaker: So I think that a great point to start would be with a little bit of history of angiotensin II.
Speaker: Some of our listeners might be aware that this is not a brand new drug.
Speaker: It was around before, and somehow you found it, resurrected it, and brought it back into play in critical care.
Speaker: Can you tell us about that?
Speaker: Sure, absolutely.
Speaker: And before we get rolling, let me just disclose a little bit further.
Speaker: I know that you had mentioned this at the beginning, but just everyone's absolutely clear that
Speaker: Currently, I am on sabbatical working as the chief medical officer of La Jolla Pharmaceutical, and La Jolla Pharmaceutical was the sponsor of the 8-Dose-3 trial and the manufacturer of angiotensin-2, trade name Geopreza.
Speaker: So everyone should recognize that despite 20 years in academics and being a professor, I currently work at this company, and people should frame all of their opinions based on the fact that this conflict
Speaker: exists, I will embark to try and keep this in a very scientific conversation.
Speaker: But I do want to let the listeners know.
Speaker: Thank you.
Speaker: Thanks for that.
Speaker: So basically, the history of angiotensin II, we've all learned in medical school, and it's really quite remarkable.
Speaker: It was first really discovered from the goldblatt kidneys, which is when you took a clamp on the renal artery and induced renal artery stenosis.
Speaker: And obviously, those animals became hypertensive.
Speaker: And over time,
Speaker: they discovered renin and of course angiotensin-1 being converted to angiotensin-2.
Speaker: And that discovery occurred in the late 1930s, which is kind of impressive what people were able to do almost over 100 years ago.
Speaker: And then peptide chemistry got sufficiently good enough that in the late 1950s in Basel, Switzerland at Sibahigi and also at the Cleveland Clinic,
Speaker: they were able to synthesize the first angiotensin II in the late 50s, and that was bovine angiotensin.
Speaker: So it wasn't human.
Speaker: The peptides required to make the human peptide were not sufficiently robust enough for them to do it.
Speaker: So they made a form of bovine angiotensin II, which was quite potent and entered clinical practice.
Speaker: in the 1960s.
Speaker: In fact, the first large trial of angiotensin II was actually published in an obscure journal called JAMA, which as a joke, of course, is not obscure and was not obscure in the 1960s.
Speaker: And there was a paper demonstrating that angiotensin II was quite effective in shock.
Speaker: And if you look from the 1960s, you'll find many, many articles of angiotensin II being used in shock and being quite effective.
Speaker: And it was primarily utilized in those days for catecholamine rescue.
Speaker: It ended up not being favorable for first-line therapy.
Speaker: And it was used primarily in clinical practice for patients with post-op cardiac vasoplegia.
Speaker: When you travel around, which I had the opportunity to do in developing the Atheros III trial,
Speaker: The only people who'd ever used bovine angiotensin II who were still alive and practicing, or at least the ones I had met, all of them were people who worked in the cardiac ICU.
Speaker: And I met one person in the US and around 10 in Europe
Speaker: And that's where they said it worked well.
Speaker: And in fact, one person got quite upset with me and said, how come you took it away?
Speaker: Which was kind of amusing since it was removed from the market well before my interest began into it.
Speaker: And sometime in the late 90s, Ciba, which was the company that made bovine angiotensin II, was bought by Novartis.
Speaker: And as part of this sort of very interesting story going back in time, I had the opportunity to meet someone who worked at SIBA when the Bartas bought them, who worked in the Angiotensin II scientific arm.
Speaker: And I asked her, I said, you know,
Speaker: What happened was the drug was drawn for safety issues, which I think is an obvious important issue.
Speaker: And they said, no, we had detected no safety issues whatsoever.
Speaker: The drug was actually doing reasonably well as a product for the company.
Speaker: But they made a decision that it wasn't making enough money, which is, I know, an extraordinarily weird thing to hear.
Speaker: But this is what's common in the business world.
Speaker: And Novartis was primarily interested in SIVA's outpatient drugs and did not have a large inpatient commercial group.
Speaker: And so they killed the drug and they withdrew the NDA, meaning that they withdrew the drug actively from the market.
Speaker: And this was something which, you know, is not published anywhere.
Speaker: This is sort of talking to people and understanding what happened.
Speaker: And this all occurred and angiotensin II, which was available at the bedside, went away.
Speaker: And then my interest in angiotensin II began with Ronaldo Bolomo's paper where he took sheep and as a nephrologist and an intensivist, my interest was in acute kidney injury.
Speaker: And he did a very elegant study where he took sheep and they implanted into the sheep multiple monitors surgically and then they allow the sheep to heal up and then they give the sheep an E. coli intravenous infusion.
Speaker: And
Speaker: In this infusion, Rinaldo's group, Clive May and others down in Melbourne, Australia, demonstrated quite beautifully that in shock, the renal blood flow goes up, not down.
Speaker: And in fact, as an aside, which doesn't necessarily have anything to do with angiotensin II per se, but we had largely been told that
Speaker: real blood flow in shock goes down and that's why you get acute tuberculosis.
Speaker: And in fact, when you look at animal studies and animal models and you look at the human data, quite the opposite is true.
Speaker: Real blood flow goes up in vasodilatory shock when it's resuscitated.
Speaker: And what you find though, is that the creatinine clearance still goes down, the FINA goes down, and this is largely due to microcirculatory defect in efferent vasodilation.
Speaker: So in essence,
Speaker: being in shock is like getting an ACE inhibitor for the kidney.
Speaker: And what Rinaldo beautifully showed in a follow-up trial is when you give angiotensin to these septic sheep, you restore GFR, urine output goes up, creatinine clearance goes up, and everything gets better.
Speaker: And so I looked at this animal study and I thought, well, this is very interesting.
Speaker: And I started to read about it.
Speaker: And as you read backwards and you start taking papers and having them get
Speaker: flipped over from microfiche, which was sort of an amusing process.
Speaker: Some of your listeners don't know what microfiche is, but there are all these old archive pieces of data.
Speaker: And what we find from those is that angiotensin II was widely used and a rescue drug for shock.
Speaker: So I wanted to bring angiotensin II into a study to use it for acute kidney injury, but the problem was that we didn't even know what the appropriate dose would be.
Speaker: So we had one big question is what's the correct dose?
Speaker: And the second issue is that if you want to give it for acute kidney injury, we at the time that I did my pilot trial did not have very effective biomarkers to give you an early identification point for which you would actually start the infusion.
Speaker: And in fact, when you're bringing a new drug out, usually the safest way to do it is to do it in very sick patients.
Speaker: And because there were very compelling data in the bovine angiotensin that it could rescue patients with catecholamine-resistant hypotension, that's the study we embarked out to do.
Speaker: And that's how the ATHOS pilot trial was initiated.
Speaker: So by now, the peptide chemistry had gotten good enough that they were able to make human angiotensin, too.
Speaker: So we opened up an IND, we went through our B process, we acquired human angiotensin II, and we did a 20-person pilot trial in patients who were on high-dose vasopressors.
Speaker: And effectively, that means they were at least on 20 mikes per minute of norepinephrine.
Speaker: For those of you who dosed some mikes per kilo per minute, it was all around 0.2.
Speaker: And in our group at George Walsh at the time, we used vasopressin for patients who were at this dose.
Speaker: So nearly all the patients, I believe it was 19 out of the 20, were on vasopressin at the time.
Speaker: And what we found in that pilot trial was that angiotensin II performed exactly like it did historically, and it was able to raise blood pressure.
Speaker: And I think a lot of people have sort of made the point that, well, you know, Mink, I mean, the number one selling antihypertensive in the world blocks the angiotensin II.
Speaker: It makes sense that angiotensin II would raise blood pressure.
Speaker: And I think that's right.
Speaker: I largely agree with that, of course.
Speaker: But it was not entirely clear to me that when you have profound vasodilatory shock and your nitric oxide is massively upregulated,
Speaker: whether you could actually get any lift.
Speaker: And what we found is 100% of the patients who got drug enjoyed a blood pressure increase such that we were able to rapidly down titrate the norepinephrine.
Speaker: But the really striking finding in a rather small trial was that two out of the 10 patients were exquisitely sensitive to angiotensin II.
Speaker: So, Sergio, let's imagine a very inappropriate experiment where I take one of your young trainees and I give them 10 grams of enalopril, thereby shutting down all their angiotensin tube production.
Speaker: So, in order for me to give them the replacement dose of angiotensin that would be in their body, they would require five nanograms per kilo per minute.
Speaker: And what we found is that these two patients that were both north of 20 of norepi
Speaker: once they were on angiotensin II, they required less than the physiologic replacement dose, 2.5 nanogastrokiloprimenib, and all their other vasopressors came off, and they were hypertensive.
Speaker: And I did not have a provision for this in my protocol.
Speaker: I don't know who would have anticipated this, to be fair.
Speaker: and I had to stop the infusion early and report it as an adverse event.
Speaker: And then when I took the replacement dose of angiotensin 2 away, their background vasopressor just came back immediately.
Speaker: And so it wasn't just that the patients were getting better.
Speaker: And so one of the key findings of a very modest size pilot trial was that there was a group of patients in whom
Speaker: physiologic dose replacement angiotensin II completely altered their hemodynamic profile in a very positive way.
Speaker: And if you read that pilot trial that was published in Critical Care Medicine in 2014, you'll note that 20% of the patients receiving angiotensin II have the adverse event of hypertension in a shock trial, which I would argue is pretty uncommon.
Speaker: And so, you know, yeah, go ahead.
Speaker: I'm sorry, I was going to, and maybe we don't know this yet, but do you know, was there something particular about their angiotensin 1 to angiotensin 2 profile or something in particular that you found that would predict that?
Speaker: Yeah, so this is a great question.
Speaker: And so at the time, it was my suspicion that they had been receiving ACE inhibitors and got sick.
Speaker: So one patient was a diabetic.
Speaker: The other one had a class two heart and was a heart failure patient.
Speaker: And I said, you know, the likely scenario here is that these folks had been suppressed, not unlike the way we treat an Addisonian patient who's been taking steroids or some other disease.
Speaker: And, you know, we wrote that up in the paper and that's basically what we put down.
Speaker: And if you look at ACE inhibitors,
Speaker: The half-life of these drugs are quite long.
Speaker: And so it was very rational to us that this was the case.
Speaker: And the reviewer at critical care responded back.
Speaker: And it turns out that the reviewer who gave me all this trouble was actually a dear friend of mine, Louis Forney.
Speaker: And he was a good friend then, but fortunately he was anonymous because he really criticized the heck out of us.
Speaker: And he said, you know, okay, this is a reasonable hypothesis, but were they, or were they not receiving angiotensin?
Speaker: And, um, um,
Speaker: inhibitors, ACE inhibitors.
Speaker: And so, you know, I sent my fellow to go back and, you know, pull the charts and we really couldn't find it in the MAR, in the medical reconciliation.
Speaker: So I wrote back to the journal and said, look, you know, this is America, you know, our healthcare system is not as, you know, robust with medical records as Europe.
Speaker: This is a reasonable hypothesis.
Speaker: And then they wrote back quite sharply, were they or were they not receiving ACE inhibitors?
Speaker: So then I took my fellow, I asked them to get a group of medical students together, and I informed them that they needed to go to the Walgreens, the CVSs, and all the pharmacies in the area, find all the outpatient doctors.
Speaker: And I said, this is a great hypothesis.
Speaker: You guys need to find the ACE inhibitor exposure.
Speaker: I'm sure it's there.
Speaker: So I sent them off on their mission, and they came back two or three weeks later, and they said, Mink, we can't find it.
Speaker: So, you know, we wrote this very sort of peculiar article
Speaker: you know, sentence in the discussion saying, we think it's ACE inhibitors, but we're not sure.
Speaker: And it was actually very good that this happened because we didn't understand this.
Speaker: And I started reading a lot more about angiotensin I, angiotensin II, and ACE.
Speaker: And as a nephrologist, I thought I knew this system pretty well.
Speaker: But one of the things that
Speaker: I knew, but I had forgotten is that angiotensin converting enzyme is not primarily a plasma enzyme.
Speaker: That enzyme lives on your endothelium, mostly in your pulmonary and your renal endothelium, but mostly in your pulmonary endothelium.
Speaker: And I thought to myself, well, maybe if you get severe endothelial injury in your lung, that would be a reason why you wouldn't be able to convert ang1 to ang2, and you would have this relative angiotensin 2 insufficiency.
Speaker: And then, you know, like I said, this whole process of angiotensin II, usually you're doing new experiments and new trials on learning.
Speaker: You know, I've had quite the opposite experience.
Speaker: I've joked with my friends and colleagues.
Speaker: I feel like this way is the lost art going into tombs and reading runes and old German texts.
Speaker: And we found a paper that was published in Circulation in 2000, wherein it's beautifully demonstrated that patients with ARDS
Speaker: their ability to convert angiotensin 1 to angiotensin 2 is linearly compromised by the severity of ARDS.
Speaker: Now, currently, in these days, we use the Berlin criteria, but back then they used a thing called the Murray Lung Injury Score.
Speaker: And what you find is the more severe your Murray Lung Injury Score, the more unable you are to convert ANG1 to ANG2.
Speaker: And when we went back to our pilot trial, both patients who had the exquisite
Speaker: sensitivity to angiotensin who both had severe ARDS.
Speaker: One was on nitric oxide and the other was just about to get flip prone.
Speaker: So we then wrote an editorial to Critical Care outlining our hypothesis that
Speaker: patients who have severe endothelial injury, particularly those with likely ARDS, are likely the ones who have this angiotensin II insufficiency.
Speaker: And we also wrote in that paper that we thought that the angiotensin I to angiotensin II ratio would be a very thoughtful way to assess this because you can't measure endothelial function very effectively at the bedside.
Speaker: So we pre-specified in the APTHOS trial
Speaker: an assessment of the angiotensin 1 to angiotensin 2 ratio as a measure of ACE activity.
Speaker: And that was one of the key things that we did in the larger phase three trial.
Speaker: This is all super interesting and I think like you said, mentioned earlier, Mink, not something that we can just read upon in a review article, so I think it's fascinating.
Speaker: So I think that it's a good point.
Speaker: I mean, now to jump into Aethos III, you just mentioned, I mean, that now you, as you designed this second or the larger trial, you were already looking at these levels.
Speaker: You want to tell us a little bit about this trial?
Speaker: Sure, and so one of the things I want to tell people about in the Aethos III trial is
Speaker: is the rationale for why the study was designed the way that it was.
Speaker: So everyone, not everyone, I should say, let me be a little more thoughtful.
Speaker: Many people have complained and said, oh, well, all you demonstrated is that the blood pressure goes from 65 to 75.
Speaker: 75 is not a blood pressure right target.
Speaker: The study is meaningless to me.
Speaker: Everyone knows angiotensin 2 makes the blood pressure go up.
Speaker: And I think that
Speaker: A reading of the abstract of the trial may allow for that type of opinion, but I think if people read the full paper and importantly read the supplement, the New England Journal asked us to write a pressee on the rationale for study design.
Speaker: And the rationale for study design was predicated on two important facts.
Speaker: Fact number one is that there has not been a single randomized controlled trial of any vasopressor that demonstrates a mortality benefit in shock.
Speaker: So while we all agree, and I would point out that I agree, and in my clinical practice I still see patients, norepinephrine is first-line therapy.
Speaker: And I agree that it should be first-line therapy.
Speaker: But that indication of first-line therapy is not based on a survival benefit.
Speaker: Everyone is familiar with the VAS data and the VANISH data, neither of which have shown an improvement in mortality slash survival with the use of vasopressin.
Speaker: In my clinical practice, I use vasopressin somewhere between 10 and 15 mics per minute of norepathy.
Speaker: That's my practice.
Speaker: And I use these drugs on a routine basis.
Speaker: I think most of us do.
Speaker: I think it's important to recognize that no vasopressor, none, has ever shown a mortality benefit.
Speaker: So when we went to FDA,
Speaker: they were acutely aware of this.
Speaker: And we said to them, we are not proposing a shock drug in the sense of this actually treats sepsis.
Speaker: So if you think about septic shock in particular, and I like to break this down into three large bins, when I care for a septic shock patient, I think about three things.
Speaker: One is hemodynamic support.
Speaker: Number two is source control.
Speaker: And number three is host response modulation.
Speaker: And so in the bin that is human dynamics, we all believe that maintaining inappropriate blood pressure is important.
Speaker: And the FDA agreed, and they agreed that the fact that there's only two classes of vasopressor available to treat a very severe syndrome would benefit from a third class of vasopressor.
Speaker: And that was the basis of designing a phase three registration trial.
Speaker: And at that meeting, when we agreed that MAP was the appropriate endpoint for a vasopressor, the question was, how can you demonstrate to us that this is a vasopressor?
Speaker: And so my initial proposal was to show catecholamine reduction.
Speaker: And I initially proposed a 50% reduction in catecholamine as being an appropriate endpoint.
Speaker: And the FDA said,
Speaker: you're telling us the drug is a vasopressor, correct?
Speaker: We said, yes.
Speaker: And they said, then you must demonstrate that the blood pressure goes up.
Speaker: Catecholamine sparing can be done with other agents through other mechanisms.
Speaker: That's not blood pressure going up.
Speaker: That could mean something that's related to blood pressure.
Speaker: We understand why you would arrive at that as a reasonable hypothesis.
Speaker: You must demonstrate to us that the blood pressure goes up.
Speaker: So we said, okay, what would you like?
Speaker: And they said, demonstrate to us a meaningful increase in blood pressure.
Speaker: And that's how we arrived at raising the blood pressure from 65 to 75 or a delta 10.
Speaker: But we informed the FDA that it is not standard practice in all ICUs to raise people's blood pressure to 75 for an extended duration of time.
Speaker: and that even though the sepsis spam as far data demonstrated no harm, most physicians will not maintain a map of 75 to 80 in their shock patients.
Speaker: Some might, but this is not standard practice.
Speaker: So we arrived at this three hour trial where angiotensin II versus placebo is titrated in order to demonstrate the blood pressure goes up for three hours with the standard of care vasopressors staying still.
Speaker: Therefore, ensuring that the only thing that could be causing the blood pressure to go up is the angiotensin II.
Speaker: And then from three hours to 48 hours, the clinicians could titrate the angiotensin II as they saw fit, thereby demonstrating catecholamine sparing, which is why our secondary endpoint was cardiovascular sulfoscore.
Speaker: Now, we actually asked them to actually look at norepinephrine dose, but they said they wanted a consensus guideline as a secondary endpoint, hence cardiovascular score.
Speaker: So the trial was essentially a demonstration of blood pressure increase as per our negotiation with FDA.
Speaker: and catecholamine reduction.
Speaker: And we demonstrated both of those in ATHOS-3.
Speaker: And so that was the rationale for the trial.
Speaker: Now, many people have also stated that what we should have done is a head-to-head trial instead.
Speaker: And the reason why we did not do that, and it's very important, the other large consideration for FDA, of course, is efficacy.
Speaker: But I think people underestimate and do not think about how much their
Speaker: responsibilities related to safety.
Speaker: So in order for FDA to approve a drug, they want to feel very confident that the drug is safe.
Speaker: And if you compare angiotensin II to vasopressin, as an example of a trial, what you would have is adverse events that occur on both sides.
Speaker: Well, it's very hard to ascertain what's an angiotensin II effect versus a vasopressin effect because they're both in the same drug class.
Speaker: They're both vasopressors.
Speaker: So they asked us to go against placebo.
Speaker: And the rationale, of course, when you do a placebo-controlled trial is if you see an imbalance in adverse events, you can feel much more confident that those adverse events are occurring due to the drug.
Speaker: Now, one of the things that was very striking, and I think one of the things that pleased me the most about the study, is that adding angiotensin II, a potent vasopressor, resulted in fewer numerical serious adverse events than those patients who were in the placebo arm.
Speaker: And in critical care, there's no free lunch.
Speaker: If you add dobutamine, you're not surprised when you get tachycardia and hypotension.
Speaker: If you add milrinone, not surprising for the same.
Speaker: We are used to paying the cost of adding a therapy.
Speaker: And it's not that I think that angiotensin 2 doesn't have toxicity.
Speaker: I'm confident that it does.
Speaker: But because you're able to use angiotensin 2 and decrease the dose of toxic catecholamines, you get the offset wherein you get a similar safety profile.
Speaker: And so I think in aggregate, the way people should view ethos 3 is not that it was trying to be vast.
Speaker: It wasn't.
Speaker: This was a very complex
Speaker: well-designed trial that was set out to do one and only one thing, which is to demonstrate safety, which we did, and efficacy as a vasopressor.
Speaker: And that's what it was set up to do.
Speaker: Yeah.
Speaker: And I think that's a very important point that I've also, I mean, discussed with many people and 100% agree, understanding what we're trying, what we're asking from our trials.
Speaker: I mean, every trial can't answer every question, right?
Speaker: And I think that this, from my point of view, opens the door.
Speaker: It's not a definitive study, like you said, but it opens the door.
Speaker: And I think that now we have additional data that's coming up.
Speaker: And I don't know if you want to jump now and maybe tell us a little bit, Mink, about the recently published data in critical care medicine regarding the outcomes in those patients who had vasodilatory shock and were also initiated on renal replacement therapy.
Speaker: Yeah, thanks very much, Sergio.
Speaker: I want to just talk about
Speaker: subset data before we talk about this particular subset and my view of subset data.
Speaker: So many people feel that subset data, even if it was pre-specified or post-hoc, is meaningless.
Speaker: And I couldn't disagree more.
Speaker: I think one of the things that people need to recognize is that when you do a registration trial,
Speaker: for the FDA and for a regulator, they insist that you pre-specify important subgroups.
Speaker: And the reason is not just to maybe find hypothesis generating groups that may enjoy benefit, but the most important thing is to identify subsets from which they might be harmed.
Speaker: That's why these subsets are pre-specified.
Speaker: So we identified multiple subsets, and I'll tell you about the results of those findings, but the way, in my view,
Speaker: you should look at the subset data is to inform you of whether there is a harm signal.
Speaker: We know that for broad classes of drugs that there's certain groups of patients you should avoid.
Speaker: And you avoid them because if they get that drug, bad things happen.
Speaker: Similarly, you can imagine a group of patients where an angiotensin 2 isn't good for them.
Speaker: So the first subset that we looked at, and these data were basically
Speaker: were presented in abstract form were the group of patients with high severity of illness.
Speaker: So we want to know as intensivists, does a high Apache 2 score identify a group of patients who does better, does worse, or does about the same?
Speaker: And what we showed is that for those patients, and this is a pre-specified analysis with an Apache 2 score greater than 30, they enjoyed a survival benefit.
Speaker: And that's what you would expect.
Speaker: And that survival benefit was statistically significant with a p-value of 0.04.
Speaker: And so more severely ill, they're outrunning you.
Speaker: Does a rescue vasopressor help you?
Speaker: The answer is yes.
Speaker: And importantly, in the patients with an Apache score less than 30, it's not zero sum.
Speaker: We just show no benefit, but we do not show harm.
Speaker: Similarly, we looked at patients who had a mean arterial pressure less than 65 at baseline.
Speaker: Now, of course, we all know that in surviving sepsis, the European guidelines, and in every single shock guideline, the baseline map that you should achieve is 65.
Speaker: And when FDA asked us to pre-specify this group of patients, I said, look, guys, this is an RCT.
Speaker: These investigators are not going to put in patients who are on high-dose norepinephrine vasopressin who are not achieving a MAP less than 65.
Speaker: I said that in my clinical practice, I very rarely let people be less than 65, and I will use more catecholamine and vasopressin to do it.
Speaker: And FDA said, you know, Mink, that's great.
Speaker: We really think you have a nice opinion.
Speaker: Do it anyway.
Speaker: And I was, of the many things I've been humbled on in this trial, and this is one of them, fully one third of the patients in the trial had a baseline MAP less than 65.
Speaker: One third.
Speaker: I was stunned.
Speaker: Because this is a randomized control trial that occurred in some of the best centers around the world.
Speaker: United States, Canada, Australia, New Zealand, you know, the UK, Germany.
Speaker: Brussels and Belgium and France and Finland.
Speaker: And these are all the top centers.
Speaker: One third of the patients have a baseline map less than 65.
Speaker: And what we demonstrate is that those patients have a much better response and blood pressure.
Speaker: You can now get them above 65 because many of these folks are generally viewed as moribund.
Speaker: You didn't think anything could happen.
Speaker: And we actually showed a very nice survival trend improvement.
Speaker: And these data have also been published in abstract form.
Speaker: But importantly, we also looked at this group of patients who mechanistically were linked to angiotensin II.
Speaker: This is the group of patients who have an angiotensin I and angiotensin II ratio that's high.
Speaker: So just by way of background, if you take the CIRA of healthy volunteers or look at the angiotensin I and angiotensin II ratio in otherwise healthy hypertensive patients, what you find is a normal ratio is around 0.5.
Speaker: which means that you have around two times as much angiotensin II as angiotensin I normally.
Speaker: In the trial, we demonstrate that the median value, this is a pre-specified analysis, of angiotensin I to angiotensin II ratio is 1.6, which means that in shock, your ACE function is highly disordered.
Speaker: And this is almost certainly due to endothelial dysfunction.
Speaker: This alone, I think, is a very important finding that people are not really focusing on.
Speaker: in shock your ace function is defective in the subset whose median ang1 ang2 ratio is above 1.6 they enjoy a highly statistically significant survival benefit and then those patients with a ratio less than 1.6 there's no difference but there's no harm and the most recent data that you alluded to that we were really excited about is we looked at patients who were
Speaker: had acute kidney injury, and who were on dialysis at baseline.
Speaker: So you're in the trial, you're on a lot of vasopressor, you're already on some form of renal replacement therapy.
Speaker: Now, in this patient population, they have an even more disordered ACE defect because their median value of ANG1-ANG2 ratio is north of two.
Speaker: I believe it was around 2.3 or 2.4.
Speaker: So this is some of the most disordered patients in the trial.
Speaker: They have the most defective ANG1-ANG2 ratios, meaning that they're angiotensin II relatively insufficient.
Speaker: And in the group on dialysis that's hit, it receives angiotensin II exogenously,
Speaker: They enjoy a substantial mortality benefit to the tune of a P. value of 0.01.
Speaker: This holds up in a multivariate analysis, but most importantly, quite strikingly, they recover from dialysis more rapidly than placebo.
Speaker: Half the patients who received angiotensin 2 are off renal replacement therapy at 7 days versus 20% in the other arm.
Speaker: And as a nephrologist who spent a lot of time in the AKI world, I did not think it was possible to help people once they were on dialysis.
Speaker: I've been teaching for about 20 years that once they're on dialysis, it's too late.
Speaker: You miss the boat.
Speaker: You fail to resuscitate them.
Speaker: You fail to do all the things you need to do to get them better.
Speaker: And I was really quite humbled with this result.
Speaker: And, you know, people have been
Speaker: sort of giving us a hard time saying, just increasing blood pressure doesn't really do anything for you.
Speaker: There's no cost savings.
Speaker: Well, I'm here to tell you that as an AKI expert, that coming off of dialysis is a good thing, and not being a CKD patient is a good thing, and not being an ESRD patient in the future is a good thing.
Speaker: And not surprisingly, those patients who come off of dialysis faster have less ventilator days and spend less time in ICU.
Speaker: So
Speaker: We will hope to go on and further validate this because it was a subset, it was a post hoc analysis, so we are obliged to do another study and show that in the future.
Speaker: But these findings are mechanistically linked because we know those patients who are angiotensin II deficient cannot maintain efferent tone, they cannot maintain GFR, and we pre-specified that we thought this ang1-ang2 ratio might be important.
Speaker: And so in aggregate, I think that if you look at all the subset data, I think that our conclusion, and I think people should feel free to challenge this and give another view of it, is that angiotensin II is not just another vasopressor, in my view.
Speaker: It's, in many patients, the missing vasopressor.
Speaker: Not another vasopressor, it's a missing vasopressor.
Speaker: And the subset data, yeah, go ahead.
Speaker: So go ahead, go ahead.
Speaker: Sorry, go ahead.
Speaker: No, I was just going to say that.
Speaker: And then as a clinician, we know that it will help you raise blood pressure.
Speaker: It'll help you unload your catecholamines.
Speaker: There are important subsets where they enjoy a survival benefit.
Speaker: But most importantly, there is no subset for which we have found that angiotensin 2 creates harm.
Speaker: And that to me is the most important thing.
Speaker: Of all the things that exist, yes, we always wanna go for mortality benefit.
Speaker: Yes, we want fewer ventilator free days.
Speaker: Yes, we want to come off with dialysis good.
Speaker: Those are all good things.
Speaker: But for me to bring a drug to market and have a drug that is now available that we cannot demonstrate harm, that to me is a really important takeaway finding because that's what the clinician at the bedside needs to have comfort with.
Speaker: Yeah, and I think that historically, for some of our younger viewers, there have been compounds that have been studied in sepsis that did raise blood pressure, but also increased mortality.
Speaker: So this is not something that just we should assume that, oh, anything that raises blood pressure in a shock state is probably not going to be harmful because there have been drugs that actually have been harmful prior to
Speaker: for other mechanistic reasons.
Speaker: So that's, I think, like you said, make a very important point.
Speaker: One question I do have, and it's one of the clarification for the audience, is in the subset of patients that you looked at with the benefit, with the renal replacement therapy, that excluded patients who were ESRD prior to getting sick, correct?
Speaker: Yes, that's right, and that's an important point to make.
Speaker: Yes, the ESRD patients were excluded from that analysis because obviously they didn't have the opportunity to get better.
Speaker: But it was a very small number of patients in the trial who had ESRD.
Speaker: Excellent.
Speaker: So I think that, as you were discussing, Mink, there's a lot of very interesting aspects about agitensin II.
Speaker: Like you mentioned, it's a different pathway.
Speaker: So it could be viewed, I mean, from a physiological standpoint for the right patients as a
Speaker: complementary approach that might be very targeted in some subsets.
Speaker: But I guess in terms of real life and practicality, now it's approved, it's commercially available.
Speaker: In your view today, how would you insert Jepressa or Aditansin II into the treatment, into the paradigm treatment of shock?
Speaker: Yeah, thank you, Serge.
Speaker: I think that's a really important question.
Speaker: So let me just sort of share with you a bias that I have.
Speaker: And I don't think everyone agrees with this, but let me share it with you because I think it's important for the recommendation that I'll give based on the data.
Speaker: Generally speaking, it's my view that single bullet, silver bullet therapies are no longer the key to gaining significant traction in difficult to treat diseases.
Speaker: So if you sort of look at HIV, we had many, many drugs that were available that could decrease viral load.
Speaker: It wasn't until we had multi-mode therapy that we got traction.
Speaker: The same is true for hepatitis C.
Speaker: And then people say to me, well, Mink, those are infectious diseases, it's different.
Speaker: And I say, okay, well, if you look at something like oncology, even people who have, who respond to Gleevec, don't get Gleevec alone.
Speaker: You need more than one drug.
Speaker: No one just gets cyclophosphamide.
Speaker: And people say, yeah, fair enough, but that's cancer.
Speaker: So I would point out an inflammatory disease.
Speaker: So we think that vasodilatory shock is largely inflammatory disease.
Speaker: There isn't a patient I know who's just getting better on Humira for rheumatoid arthritis.
Speaker: They're not just getting better on steroids alone.
Speaker: They're not just getting better on methotrexate alone.
Speaker: What we find is a combination of therapies used in lower doses, decreases toxicity, and you get synergy.
Speaker: And I think the best example of this is in hypertension.
Speaker: All of us treat hypertensives.
Speaker: There's nobody who is out there who has a patient on nine grams of metoprolol.
Speaker: That's not what we do.
Speaker: And then you don't see someone on 9 grams of metoprolol, even if they existed, then get added on to labetalol.
Speaker: We don't see patients walking around who are on labetalol and metoprolol.
Speaker: But in the ICU, it's very common for someone to say, well, they're on norepi, they're failing, let me add epi.
Speaker: This to me is deeply illogical.
Speaker: I don't understand it.
Speaker: I don't understand how epi is going to save you and nor epi is not saving you because there's some beta receptor out there that you haven't found.
Speaker: This doesn't make any sense to me.
Speaker: We don't do this in any other disease.
Speaker: And so it's my very strong view that multimode therapy is rational.
Speaker: And what we saw in the clinical trial is that patients were
Speaker: 99% of patients in ATHOS3 were on norepinephrine, and another 70% were on vasopressin.
Speaker: And we added angiotensin II to them.
Speaker: And I think this is very logical.
Speaker: If you think about neurohormonally, how we all take care of ourselves, we used a balanced approach.
Speaker: I mean, take, for example, Sergio, imagine one morning you come in, you're on service, you haven't had your coffee,
Speaker: You haven't had a glass of water all day.
Speaker: It's now three o'clock in the afternoon.
Speaker: You haven't had a thing to eat or drink.
Speaker: You're not hypotensive.
Speaker: And neurohormonally, you've defended your blood pressure through heart rate and cardiac output.
Speaker: And it is almost certain that you have
Speaker: increase the production of catecholamines, vasopressin, and angiotensin to defend your blood pressure.
Speaker: And to me, this is what I think we should be doing clinically.
Speaker: If people are failing current drugs, then it makes sense to me to use multimode therapy.
Speaker: And I think that's the approach that we did in our clinical trial, and that's what I would like to see people do clinically.
Speaker: To me, this is a highly logical way of moving forward.
Speaker: So in terms of just some practical points, a lot of listeners, I'm sure, have not had the opportunity to utilize the drug.
Speaker: I know that the recommended dosing is in nanograms per kilogram per minute and that it's recommended that you start at a dose of 20 nanograms and increase by 15.
Speaker: And then the range really seems to be for utilization between 2.5 and 40 nanograms per kilogram per minute.
Speaker: Is that correct?
Speaker: That's right.
Speaker: And what about... So let me tell you what... Go ahead.
Speaker: Yeah, go ahead.
Speaker: No, no, go ahead.
Speaker: What we saw in the clinical trial and the use that we typically saw is that when patients got started on angiotensin II,
Speaker: if they had a brisk response, what we typically saw people do is come off of the high-dose epi first for a lot of obvious reasons.
Speaker: Typically, when you're on high-dose vasopressors and you're on epi, typically you see a lot of the side effects of epi.
Speaker: So what we saw in the clinical trial is when there was a blood pressure response is moving the catecholamines rapidly out of their toxic range.
Speaker: And then once the catecholamines are down below a toxic range, and in my view, that's sort of getting your epi off and your norepi down to around 20 mics per minute or 0.2.
Speaker: And that's what we saw in the clinical trial people would do.
Speaker: And then what we saw is that depending on
Speaker: people's views of which vasopressor they like more or not, meaning vasopressin.
Speaker: The vasopressin would come off quickly or some people will leave it on longer and then take all three down together.
Speaker: I think all those approaches are reasonable.
Speaker: I think that, of course, the bedside clinician, once they get
Speaker: down to lower doses of each, which is what we saw in the clinical trial, they'll use their bedside acumen to determine what they need more or less of.
Speaker: And I think a lot of it will determine if they're having tachyarrhythmias or not, or if they're having any side effects due to things which are catecholamine related.
Speaker: And so what we saw in the trial is adding angiotensin to, and then when there was a response, being able to move down off of the others in pretty short order.
Speaker: And I think that in terms of how I'm thinking about this drug based on what we discussed and what I've read, you were very clear, Mink, that this is not your go-to drug for everybody with distributive shock.
Speaker: It's a part of a multimodal approach, especially when people start failing our first-line therapy, such as norepinephrine.
Speaker: There might be some subsets of patients who hopefully will get more data that might benefit even further.
Speaker: But right now in 2018, as we introduce this to our clinical practices, obviously a lot of the discussion is around value.
Speaker: And I look at value as patient outcomes over cost.
Speaker: So things that improve patient outcomes or things that decrease cost or hopefully both are things that I think are easier to introduce and support with value.
Speaker: What would be your value proposition in 2018 for this new drug?
Speaker: Yeah, I think that's a really important question.
Speaker: And given where we are in health care,
Speaker: and that we've all become appropriately cost sensitive.
Speaker: This is the question.
Speaker: And so I'll tell you what different groups are doing now.
Speaker: And most people are using angiotensin II on label, which means that it's norepinephrine, vasopressin, they add angiotensin II.
Speaker: And if you look at the label, and it's not so easy to find, but what you'll find is that if you want to get value from angiotensin II, you really need to use it before they're on 50 of norepia or 0.5.
Speaker: What you see in the label is patients who start angiotensin II before you're on very high-dose vasopressors get a much more robust blood pressure response.
Speaker: And we know that when you get a more robust blood pressure response, everything else gets better more rapidly.
Speaker: And that's in the label, although it's not really clearly identified.
Speaker: And I think that the approach that we saw in the clinical trial was exactly this, norepinephrine, vasopressin, and then before going back to another catecholamine, going to angiotensin II.
Speaker: And when that happens, what we find is this nice trend line towards survival benefit, which is also in the label.
Speaker: But more importantly, in these important subsets that we have published, you also enjoy a survival benefit.
Speaker: I will say, though, that what we've also seen is that
Speaker: The average number of days in the clinical trial for which people need angiotensin 2 is around two days.
Speaker: And, you know, let's be very direct about this surgery.
Speaker: Let's not beat around the bush because I think people want to know what the price is and they want to know how much things cost.
Speaker: So angiotensin 2 per vial and for 90 plus percent of your patients, they need one vial per day.
Speaker: is $1,500 a vial.
Speaker: And a lot of people sort of say, well, that's a lot of money.
Speaker: And there's no getting around the fact that it's certainly not as cheap as norepinephrine.
Speaker: It is what it is.
Speaker: And if you look at the cost of vasopressin, so there's usually three vials of vasopressin in a bag.
Speaker: And so generally speaking, angiotensin II is twice the cost of vasopressin, although different markets, different hospitals, this may vary.
Speaker: And I think a lot of people
Speaker: still say, hey, that's very expensive, although I think other people were expecting Zygris pricing, to be fair.
Speaker: And for those of you who don't know what Zygris was, it was a drug that came with enormous sticker shock.
Speaker: But as a company, I will say that it being 20 years after Zygris and being, you know, half its cost was something that as a company we were very proud of because we wanted to get this drug to patients because we think that matters.
Speaker: And what we have seen some centers do, and by no means am I saying this is what people ought to do, but because most patients are on vasopressin for three to four days, we've seen clinical pharmacologists do the math and say, well, essentially, these are the same.
Speaker: And I think that's something that every center will have to sort out for themselves to make a decision on what the value proposition is.
Speaker: The SACHA data that was just published in the Cleveland Clinic shows that around 40% of patients who receive vasopressin get a blood pressure response.
Speaker: In ATHOS-3, the number was 70% and 80% at one hour.
Speaker: So I think that people are getting into this habit of pitting in their brain angiotensin II versus vasopressin.
Speaker: And because there's costs associated with both of them,
Speaker: they're swapping them.
Speaker: But I'll be honest with you, it's my view that multimode therapy makes sense.
Speaker: So in 70 years, whenever it is, or 10 years or five years, or who knows when these things work out because vasopressin now is a branded generic and I don't know how long their IP is, but at some point when all these drugs in the far future are generic, I think people will put them together much earlier, much more rapidly because it's highly logical.
Speaker: I think in an environment,
Speaker: where costs are there, I think people have to think more thoughtfully about it, and that makes sense to me.
Speaker: So what I would say is that the value proposition, in my view, is exactly as it was used in the ATHOS-3 trial, which is to use it in the third-line position, but not when the patient is dead already.
Speaker: And I think people know what I'm talking about who are intensivists.
Speaker: If you're going to use it, use it early third-line like it was used in the trial if you want to see a similar kind of benefit.
Speaker: And I think that that makes a lot of sense.
Speaker: And I think that, like you said, in terms of adding vasopressors, which is no different from no vasopressor to your first vasopressor, time does matter.
Speaker: And I think that we need to do that in a timely, it's a time-sensitive intervention.
Speaker: And the same thing in terms of adding a second vasopressor or a third vasopressor.
Speaker: We configure those things pretty quickly.
Speaker: And I think that I agree, Mink.
Speaker: We should be very, very sensitive of that timing.
Speaker: Well, this has been a fascinating conversation.
Speaker: I think that we could keep going for a long time.
Speaker: But I do want to thank you for...
Speaker: Sharing with us all this information about Angitensin II, I'm sure that all the listeners will be very interested in learning as new data comes.
Speaker: Keep learning about this drug, start utilizing it, and finding, like you said, the best profile of patients that really would gain the greatest benefit from this new treatment.
Speaker: One of the things that we usually do in critical matters is at the end, tap into the wisdom of our guest and talk about a couple of topics that are a little bit not medical, but still related to the practice of critical care.
Speaker: Would that be okay?
Speaker: I'd be delighted.
Speaker: So the first question, Mink, is what book or books have influenced you the most, or if you rather, what book have you gifted most often to others?
Speaker: So the book that changed my life was Atlas Shrugged.
Speaker: It was given to me by my best friend in my second year of medical school.
Speaker: And even though I don't necessarily subscribe to all the belief structure of Ayn Rand, which I don't,
Speaker: But that book absolutely changed my life.
Speaker: It changed the way I viewed many things and it was very inspirational.
Speaker: And I think I've gifted that book no less than 10 times in my life to people.
Speaker: And so it was actually a pivotal point in my life and my career.
Speaker: And it really had a huge impact on me.
Speaker: That's awesome.
Speaker: And we'll add all the studies that we mentioned and also the book in the show notes so our listeners can check them out.
Speaker: The second question is,
Speaker: is what do you believe to be true in medicine or in life that most other people don't believe?
Speaker: So this is gonna be very personal and it may offend some of your listeners.
Speaker: So for those of you who are listening, please don't take it too hard.
Speaker: But Serge, you know, I have a connection back to a town in South Jersey called Cherry Hill.
Speaker: And I believe the Eagles will repeat in the Super Bowl this year, this coming season.
Speaker: And I'm confident that very few people subscribe to this.
Speaker: I don't know if they subscribe to the possibility or do they wish that, but that's about two different things.
Speaker: But I think it counts both ways.
Speaker: Well, I will tell you, it is the first time in my lifetime, aside from the Eagles winning, that Cowboys fans, Redskins fans, and Giants fans were all rooting for the Eagles in the Super Bowl.
Speaker: And that will never happen again.
Speaker: Now everyone can feel free to hate us again.
Speaker: And I think that's probably largely deserved.
Speaker: True.
Speaker: I'll true that.
Speaker: And finally, what would you want every intensivist who's listening to this podcast to know?
Speaker: So I think that this is also very personal and it's something that I want people to understand that things were going very well for me in Washington, D.C.
Speaker: I had a very nice academic career.
Speaker: And the reason I took this abrupt left turn in my life to pursue energy attention to is because I thought it was very special and important.
Speaker: And I just want to share with people my thesis on why I think this is important.
Speaker: And it goes as follows.
Speaker: MAP matters.
Speaker: This is a huge bias that I have, but MAP matters and maintaining appropriate MAP matters to patients who are in shock.
Speaker: And by extension, if MAP matters for certain patients who are outrunning you, it requires the use of toxic doses of other vasopressors.
Speaker: And those toxicities are non-trivial and I think contribute to the high mortality that we see in shock patients.
Speaker: And it was this exquisite sensitivity of angiotensin II in this subset of patients that led me to make this abrupt left turn and try and work on angiotensin II because I thought it would be very important.
Speaker: I think that we owe the community more data.
Speaker: And we will endeavor to get that to the community as soon as possible.
Speaker: I think people should recall my bias, not just my potential financial conflict, but my scientific bias.
Speaker: But my my one message to all my fellow intensivists is when someone is out running you, Matt matters and this tools in the toolbox and it's going to help you.
Speaker: And I will tell you that.
Speaker: No one goes into critical care for the alcoholism or the high divorce rate for the late hours and missing all that important family time.
Speaker: We do it for the saves.
Speaker: And very few people get to talk about this.
Speaker: People who are in the military, police officers, firemen, nurses, surgeons, intensivists.
Speaker: It's a very small group of people who are in this acute care space.
Speaker: And we take on, you know, insanity in our lives and we see things that other people don't see.
Speaker: And we do it largely because we want to be able to take that person who's on a knife's edge and get them in the right direction.
Speaker: And so what I will say to my fellow intensivists out there, map matters.
Speaker: If you use angiotensin II in the thoughtful way that was in the label, you'll find that will help you.
Speaker: Excellent.
Speaker: I think that the concept of defending the map is where I think will stop.
Speaker: Mink, it was a great pleasure to have you on.
Speaker: I'm sure that we'll have a lot more conversations and hopefully we'll have you as a guest in the future.
Speaker: Thanks Sergio very much.
Speaker: I really appreciate it and congratulations on putting together a really outstanding series.
Speaker: This is one of the podcasts I listen to as well.
Speaker: So it's a real privilege for me to be someone who you've actually interviewed.
Speaker: Thank you.
Speaker: Thanks again for listening to Critical Matters.
Speaker: Make sure to subscribe to this podcast on iTunes or Google Play.
