Become a Creator today!Start creating today - Share your story with the world!
Start for free
00:00:00
00:00:01
Angiotensin II for Vasodilatory Shock: 2019 Update
10 Plays6 years ago
In this episode of Critical Matters, we discuss lessons learned from the clinical use of Angiotensin II (GIAPREZA™), which was approved for use in patients with vasodilatory shock a little over a year ago.
Our guest is Dr. Lakhmir S. Chawla, Chief Medical Officer of La Jolla Pharmaceutical in San Diego, California. Dr. Chawla was the designer and lead investigator of the ATHOS (Angiotensin II for the Treatment of High Output Shock) trial which results led to the ATHOS 3 trial, (The Phase 3 clinical trial of angiotensin II, for the treatment of catecholamine-resistant hypotension).
ADDITIONAL RESOURCES:
ATHOS-3 Clinical Trial. Randomized controlled trial evaluating the efficacy of Angiotensin II in raising blood pressure in vasodilatory shock: https://bit.ly/2r5SpG0
Outcomes in Patients with Vasodilatory Shock and Renal Replacement Therapy Treated with Intravenous Angiotensin II: https://bit.ly/2JttWTj
Sensitivity to angiotensin II dose in patients with vasodilatory shock: a prespecified analysis of the ATHOS-3 trial: https://bit.ly/2xDVVsr
ALBUMS AND BOOKS MENTIONED IN THIS EPISODE:
The Dark Side of the Moon, Pink Floyd: https://amzn.to/2XZr34x
Wish You Were Here, Pink Floyd: https://amzn.to/2Lc2lbb
Loonshots: How to Nurture the Crazy Ideas That Win Wars, Cure Diseases, and Transform Industries, Safi Bachall: https://amzn.to/2S4IrPU
Recommended
Transcript
Introduction and Background on Angiotensin II
00:00:09
Speaker
Welcome to Critical Matters, a sound critical care podcast covering a broad range of topics related to the practice of intensive care medicine.
00:00:17
Speaker
And now, your host, Dr. Sergio Zanotti.
00:00:23
Speaker
Last year, we had the opportunity to discuss on an episode of Critical Matters
00:00:27
Speaker
the then recently FDA approved vasopressor angiotensin II, available as a product named Gipressa.
00:00:34
Speaker
Angiotensin II remains a novel drug within critical care.
00:00:38
Speaker
More evidence has been published since our last episode on this topic, and based on the interest of our audience, we thought it would be valuable to follow up on this particular topic with a 2019 update.
Introduction of Dr. Lakmir Chawla and His Work
00:00:49
Speaker
Our guest is once again Dr. Lakmir Chawla.
00:00:52
Speaker
He is currently Chief Medical Officer at La Jolla Pharmaceutical Company in San Diego.
00:00:56
Speaker
Previously, Dr. Chawla was a professor of medicine at the George Washington University, where he had dual appointment in the Department of Anesthesiology and Critical Care Medicine in the Department of Medicine, Division of Renal Disease and Hypertension.
00:01:09
Speaker
Dr. Chawla was also the chief of the Division of Intensive Care Medicine at the Washington, D.C., Veterans Affairs Medical Center.
00:01:15
Speaker
During his tenure at George Washington, Dr. Chawla was the designer and lead investigator of the ATHES
00:01:22
Speaker
angiotensin II for the treatment of high output shock trial with results led to the ATHOS III trial, the phase III clinical trial of angiotensin II for the treatment of catecholamine-resistant hypotension.
00:01:33
Speaker
Dr. Chawla is an internationally renowned expert in the field of acute kidney injury and was an active investigator in the fields of inflammation and acute kidney injury, acute kidney injury biomarkers, risk prediction, chronic kidney disease caused by AKI and AKI therapeutics.
00:01:49
Speaker
In addition, Dr. Chawla
00:01:51
Speaker
was an active investigator in shock, inflammation, and extracorporeal therapies, including continuous renal replacement therapy, dialysis, and albumin dialysis.
00:02:01
Speaker
Dr. Chawla is also the author of over 100 peer-reviewed publications and was previously an associate editor for the Clinical Journal of the American Society of Nephrology.
00:02:10
Speaker
Mink, welcome back to Critical Matters.
00:02:13
Speaker
Thanks, Sergio.
00:02:14
Speaker
Great to touch base with you again.
Updates and Changes in Critical Care
00:02:17
Speaker
So since we last spoke, a lot has changed.
00:02:20
Speaker
Last time we spoke, the reigning Super Bowl champions were your beloved Eagles.
00:02:24
Speaker
That has changed, but we won't go into details there.
00:02:27
Speaker
I appreciate that.
00:02:30
Speaker
Also, we have gained a lot of experience over the last 12 plus months with the use of ANG2 in real scenarios.
00:02:37
Speaker
And I also understand that there's some interesting and emerging data looking at ANG2 and different potential modalities.
00:02:44
Speaker
I think it's been a very interesting year and change since ANG2 has become available.
Historical Context and Market Dynamics of Angiotensin II
00:02:50
Speaker
And just because I know that not everyone listens to all their podcasts in the appropriate sequential order, I'll give a really brief summary of how we got to where we are.
00:03:00
Speaker
And then for those people who are all up to date, I won't make it so painful for them that they have to hear that piece all over again.
00:03:08
Speaker
I think that's excellent.
00:03:09
Speaker
Yeah.
00:03:10
Speaker
So basically, you know, the idea behind angiotensin II for the treatment of shock is not new.
00:03:18
Speaker
Andrzejotensin II was used to treat shock since 1961, which was the first paper in which it was studied in JAMA.
00:03:25
Speaker
And it had around a 40-year career as a drug that was actually indicated for the treatment of, at the time it was called hemodynamic collapse, which is another phrase for shock.
00:03:37
Speaker
And then sometime around 1995, 1999, the exact timing is not clear,
00:03:43
Speaker
Novartis, a large company, bought Sibagigi, which is the company that made angiotensin-2.
00:03:48
Speaker
Novartis appears to have had an interest in most of their outpatient drugs.
00:03:52
Speaker
And even though there was no safety issues, the drug, quote-unquote, wasn't making enough money, and the drug was withdrawn from the market.
00:04:00
Speaker
And I think the reason why angiotensin-2 was used less than, let's say, other vasopressors is because of the fashion of critical care.
00:04:09
Speaker
Many of you all in the
00:04:12
Speaker
listening to this podcast, probably not aware of this, but Sergio certainly is.
00:04:18
Speaker
We're dating ourselves a little bit here.
00:04:20
Speaker
But when we were in training, there was a very large fascination with this concept called the oxygen transport hypothesis.
00:04:27
Speaker
And basically the idea was that critically ill patients didn't have enough forward blood flow, oxygen transport, which is your cardiac output, times your saturation, times your hemoglobin in grams.
00:04:40
Speaker
And that if you increase this, you would improve outcomes.
00:04:44
Speaker
This was based on a paper by Shoemaker many, many years ago.
00:04:48
Speaker
And this fascination led to this real focus on inotropy in the treatment of septic shock.
00:04:57
Speaker
And this got massively unwound in the mid-1990s with the Gatotone and Hayes papers that showed that giving dobutamine to patients with shock is actually lethal.
00:05:07
Speaker
So we stopped doing that.
00:05:09
Speaker
it kind of got reinvigorated with Manny Rivers' data saying that, well, goal-directed therapy is better, you just have to do it early.
00:05:16
Speaker
And now that we have Arise, Phrase, and Process, and all put together in Prism, we've sort of walked back from that view as well.
00:05:25
Speaker
And so my sort of idea for this was we don't treat hypertension with one drug.
00:05:32
Speaker
If someone is failing 100 milligrams of BID of metoprolol, we don't put them on two grams of metoprolol.
00:05:39
Speaker
but all of us have gone from 10 of norepinephrine to 100 of norepinephrine.
00:05:43
Speaker
And so in hypertension, we use multimodotherapy.
00:05:47
Speaker
In most diseases that treat inflammation, like in motor arthritis, we use multimodotherapy.
00:05:51
Speaker
And so the idea is, let's use multimodotherapy.
00:05:54
Speaker
And that started the interest in the first pilot trial that Sergio mentioned at the beginning, and then led to the ATHOS-3 trial, where we demonstrated that angiotensin-2 has a very nice safety profile,
00:06:09
Speaker
and effectively raises blood pressure in patients with high-dose catecholamines and also causes significant catecholamine reduction.
00:06:17
Speaker
And that led to the approval of the drug.
00:06:19
Speaker
We published these data in the New England Journal of Medicine in 2017.
00:06:23
Speaker
And about a year later, we got approval for the drug.
00:06:27
Speaker
That was December 2017.
00:06:28
Speaker
And now we've been out for about a year.
00:06:31
Speaker
So I think that this is a nice update with that background.
00:06:37
Speaker
Mink, maybe we can start by just giving us a little bit of the idea of the pathophysiology we're targeting with ANG2 and then maybe the currently approved indications and how you would use it actually from a dosing perspective in the real world.
00:06:52
Speaker
Yeah, so I think that's a really good question.
00:06:54
Speaker
And I think that being out a year has helped me to understand on a personal level, not just as a person working with the science, but, you know, I'm still an active clinician and I've had the opportunity to dose ANG2 at the bedside.
00:07:07
Speaker
not as a research intervention with a protocol, but as a clinician.
00:07:11
Speaker
And so what I would say is that the main take-home from the initial pilot trial, the insight, was we did recognize early on there was a subset of patients who were exquisitely sensitive to angiotensin, too.
00:07:24
Speaker
And we've come to understand why that's the case.
00:07:29
Speaker
And so most people are aware that the endothelium and endothelial cells
00:07:36
Speaker
get damaged in septic shock and inflammatory shock.
00:07:40
Speaker
And it turns out that angiotensin-converting enzyme is an enzyme that lives anchored to endothelial cells.
00:07:47
Speaker
It doesn't do most of its activity free-flowing as an enzyme in the plasma.
00:07:53
Speaker
It does it based on your endothelium.
00:07:55
Speaker
And so when your endothelium is damaged, basically you lose the ability to convert angiotensin 1 to angiotensin 2.
00:08:03
Speaker
And so
00:08:05
Speaker
The really simplistic way of thinking about this, if you have a lot of endothelial injury, it's like you took an ACE inhibitor and you happen to be in shock at the same time.
00:08:16
Speaker
And I think anyone who's taking care of a critically ill patient with inflammatory shock knows that giving them a large IV dose of enalaprolat would probably be a really bad idea.
00:08:26
Speaker
But that's essentially what is happening with these patients.
00:08:30
Speaker
And so if you think about that and you sort of say, okay, if that's what's happening to a certain subset of patients, because not all patients with shock do this, but about 40% of them tend to have this defect.
00:08:43
Speaker
And when that happens, they become catecholamine resistant and they lose their GFR because you need angiotensin II to maintain your efferent tone in your kidneys.
00:08:57
Speaker
And so most of the patients who have this defect, and these are the Tumlin data that we're publishing in critical care, have acute kidney injury and typically severe acute kidney injury.
00:09:07
Speaker
And so what we have seen based on the data which we have published is that the patients with acute kidney injury have the largest amount of evidence of this ACE defect.
00:09:19
Speaker
And we measure this ACE defect by looking at the angiotensin I to angiotensin II ratio.
00:09:25
Speaker
So ang1 is your substrate.
00:09:27
Speaker
and two is your product.
00:09:29
Speaker
So in a normal healthy person, that ratio is around 0.5.
00:09:32
Speaker
In ATHOS, the median value was 1.6.
00:09:36
Speaker
And in patients with acute kidney injury, that median value for that group of patients is 2.2.
00:09:45
Speaker
So they have the most disordered ACE function.
00:09:50
Speaker
Simply put, patients with acute kidney injury and vasodilatory shock
00:09:55
Speaker
typically have a profound ACE defect.
00:09:58
Speaker
And when you give those folks angiotensin II, even though initially it may seem like you're trading one vasopressor for another, what you're actually doing is changing the microcirculatory flow in the body, and particularly the kidney.
00:10:13
Speaker
And in that Tumlin paper, we showed that when you treat these patients with ANG2, you actually get a robust survival advantage and
00:10:23
Speaker
most importantly in my view, because I'm a nephrologist and an intensivist and acute kidney injury is my area of specialty, it's the first time we have a drug that actually improves renal recovery.
00:10:33
Speaker
They come off of dialysis faster.
00:10:36
Speaker
So this has been, I think, the key learning in my mind in a year of being out that not only is this the data that we've published, when you talk to the people who are using angiotensin II on a regular basis,
00:10:50
Speaker
They will routinely call me up and say, hey, Mink, we had this guy.
00:10:53
Speaker
He had a lot of norepinephrine.
00:10:55
Speaker
I gave him a bunch of ANG2.
00:10:56
Speaker
Initially, it just spared the norepinephrine, but we were headed towards dialysis.
00:11:01
Speaker
I've had many people call me and say the Quentin was in, and we ended up never having to dialyze them.
00:11:06
Speaker
And that, to me, is what success looks like.
00:11:09
Speaker
And so that's been really pleasing for me.
00:11:12
Speaker
So clearly, there seems to be evidence or, like you said, I mean, understanding
00:11:18
Speaker
that the relationship between angiotensin I and angiotensin II is in a disbalanced state in these septic shock patients or in these shock patients, not only septic shock.
00:11:27
Speaker
And as most places are probably not measuring ang I and ang II, what we're learning is, would it be fair to say that what we're learning is that renal failure is a surrogate for maybe that population?
00:11:38
Speaker
So if I have renal failure in this setting, it's more likely that this is the case?
00:11:44
Speaker
Yeah, that's exactly right.
00:11:47
Speaker
We aspire to get a bedside test to clinicians so they can have this information a priori, right?
00:11:54
Speaker
So you know in advance which patient population gets the benefit.
00:11:59
Speaker
Because, look, it's very obvious to us that the landscape of the world.
00:12:04
Speaker
Nor epinephrine is very cheap.
00:12:07
Speaker
Angiotensin II is more expensive.
00:12:09
Speaker
Vasopressin is also expensive, but it's sort of used as background therapy as opposed to a titratable vasopressor.
00:12:16
Speaker
And, you know, I've had many colleagues of me say to me, you know, Mink, I've used ANG2.
00:12:21
Speaker
And a lot of times I get this incredible hyper-responder.
00:12:25
Speaker
The patients immediately respond.
00:12:28
Speaker
They come off all their stuff and they begin to get better.
00:12:31
Speaker
And then other times I use it and it doesn't seem to do as much as it did with that other patient.
00:12:37
Speaker
I just wish I knew when this would happen because I know when they have this really crisp response of getting dramatic value in helping the patient.
00:12:45
Speaker
And so we've heard the community tell us this, and we're working very vigorously on developing a test that is either the ANZ1-ANZ2 ratio, which a clinician can have, or a different test that tells you what that ratio looks like so you know.
00:12:59
Speaker
And that's not done yet, but we're working very hard on that.
00:13:03
Speaker
In the meanwhile, exactly as you've indicated, if you want to clinically make that assessment, that is the patient with shock,
00:13:12
Speaker
on vasopressors who is heading towards renal replacement therapy or on renal replacement therapy.
00:13:18
Speaker
That patient, based on our data, demonstrate ACE dysfunction and this type of physiology related to insufficient angiotensin II.
00:13:32
Speaker
And I think if we just showed a survival advantage,
00:13:35
Speaker
We may have thought this is linked to severity of illness and that's where the benefit is, but the fact that they recover renal function more rapidly in a highly sophisticated fashion, and we know how ANG2 works in the kidney, this to me is also highly mechanistic and linked to this high ratio.
00:13:53
Speaker
So if you had to be restricted in the way you use ANG2, that's where I think you have extraordinary value.
00:14:03
Speaker
And I think it's also worth pointing out, Mink, that really thinking, when I hear you talk about this and having read the Tomlin papers, and it almost seems that you think about it as treating the AKI, whether the patient is on RRT or not.
00:14:16
Speaker
So not only as something to prevent RRT, but if you're already on RRT, there's still tremendous value probably in trying to revert or shorten or hasten that recovery, correct?
00:14:26
Speaker
That's exactly right.
00:14:27
Speaker
I will tell you, I mean, this is an area for which I have been proven quite wrong, which is
00:14:33
Speaker
Slightly upsetting to me, but the result's good, so I get over it fast.
00:14:37
Speaker
You know, as an ATI expert, as someone who's worked on ATI biomarkers and CRT, I have been preaching for about 15 years that to my fellows and anyone who will listen, once you put someone on a RIT and they're in shock, you've missed the boat, you're late, you know, you weren't there in time, you didn't do all the things you were supposed to do, you're an intensivist.
00:14:59
Speaker
be intense, move your butt, you know, blah, blah, blah.
00:15:01
Speaker
I mean, I still say that and I still mean it.
00:15:04
Speaker
But the fact of the matter is, and this is what stunned me, is even if you're on renal replacement therapy, it's not too late.
00:15:11
Speaker
Now, if they've been on for four weeks, I think it's probably a different deal.
00:15:16
Speaker
But if they are just going on and been on for a few days, the Tumlin data demonstrate versus placebo, you get more rapid recovery from renal replacement therapy, fewer days on ventilator,
00:15:28
Speaker
fewer days in the ICU.
00:15:30
Speaker
So it's not just the value to the patient, which of course is preeminent, but it's value to your healthcare system.
00:15:37
Speaker
And so what we've seen is the really early adopting systems, they recognize this and they are already moving up angiotensin II in their portfolio, particularly AKI patients, because they're demonstrating value.
00:15:52
Speaker
There are multiple centers that have done
00:15:55
Speaker
medical use evaluations and in addition to a survival advantage, they're showing a value advantage.
00:16:00
Speaker
And so that's been really heartening for me.
00:16:04
Speaker
And I think that since we're talking about the value, it's important for our audience who is trying to maybe bring a new drug, any drug to that matter, but in this case, had to test them to their hospital with their PNT committee is to understand the right context in terms of what are the appropriate patients.
00:16:20
Speaker
And obviously there's a lot that we're learning.
00:16:23
Speaker
But clearly, Mink, what you're sharing here is that this would be a very particular case where you can demonstrate that by shortening duration of RRT or by preventing RRT, the cost-benefit ratio of using a more expensive drug is clearly in favor of the drug and bringing it on board for these particular patients.
00:16:43
Speaker
Yeah, I think that's exactly right.
00:16:44
Speaker
And I think that's important for people to actually know the numbers because as intensivists, we kind of know what's cheap and we know what's expensive.
00:16:50
Speaker
We actually don't know what things actually cost.
00:16:52
Speaker
So for a patient on regular intermittent hemo, even if you're doing it daily or SLED, generally speaking, that's an $1,800 to $2,200 procedure per day.
00:17:05
Speaker
If you're on CRT, nursing, fluids, machine, filters, Quentin catheter, all in, it's $4,000 a day.
00:17:10
Speaker
And angiotensin II is somewhere between $1,200 and $1,500 a day, depending on the price you've negotiated.
00:17:20
Speaker
And so if you put someone on angiotensin II, and the typical time on angiotensin II is two days, and if you save one day on dialysis, right, you are already close to revenue neutral.
00:17:33
Speaker
If you save two days, you owe me.
00:17:36
Speaker
If you get them off the vent sooner, off the ICU sooner, you owe me.
00:17:39
Speaker
And so, you know, we've actually proposed to some healthcare systems, you know, how about we give you the angiotensin II for free,
00:17:50
Speaker
and you give us the net savings in your costs.
00:17:53
Speaker
Now the problem of course is no one can actually do this because they can't actually separate the patients out and do the math.
00:17:59
Speaker
And then when we put the model in front of them, they're like, no, no, let's not do it that way.
00:18:04
Speaker
Because, you know, and so what I would say is that, you know, the thing which is really interesting about it is the big problem in my mind is the previous past history of expensive drugs.
00:18:18
Speaker
So if you have been an attending physician in an ICU for the past 10 or 15 years, you have moved a few expensive drugs into your life that have made your pharmacist really unhappy.
00:18:29
Speaker
They're usually drugs like nicartatine, Cleviprax, Presidex is a big one.
00:18:35
Speaker
And so all the pharmacist sees when the intensivist asks for this drug is all they see is dollar signs going out the door and it scares them.
00:18:46
Speaker
And they don't feel like once they have the drug in that they're going to be able to control it.
00:18:51
Speaker
And I think that this is an ongoing problem everywhere.
00:18:53
Speaker
And when I was at GW, we were certainly a forward-leaning type of ICU.
00:19:00
Speaker
But we were not this super rich hospital that could just throw cost away.
00:19:04
Speaker
So what we would do is if we wanted to bring a drug in, the pharmacist would say, OK, boys and girls, you guys want to bring in this drug?
00:19:13
Speaker
It has a price tag on it.
00:19:16
Speaker
show me how you're not going to blow up the bank, show me how this is going to be revenue neutral.
00:19:20
Speaker
And what we would do is we would pull the top 10 drugs we spent at our ICU and we would say, okay, is there places here where we're not really being efficient and are we just dosing drugs based on habit and is there a way to sort of do this more thoughtfully?
00:19:34
Speaker
And for us, this exact example is when Zygris came around.
00:19:38
Speaker
Zygris was a super expensive drug and they said, look, we can't afford to blow the bank on Zygris.
00:19:44
Speaker
So we looked at our spending patterns and we realized that, you know, we were spending a lot of money on EPO at the time because as you remember, Sergio, back in the day, we were using a lot of EPO to try to prevent blood transfusion.
00:19:54
Speaker
That fad went away.
00:19:56
Speaker
That's a fad that I actually got on and ended up not showing the benefit we had hoped.
00:20:00
Speaker
So we stopped doing it.
00:20:01
Speaker
And we said, okay, instead of giving EPO to everybody, we did give EPO to everybody.
00:20:07
Speaker
We said, okay, we're only going to give it to the patients in whom we think there's really particular benefit.
00:20:11
Speaker
And we created space.
00:20:13
Speaker
to make sure we had all the tools in the toolbox.
00:20:16
Speaker
And I think that's the right way to go to make sure everything is available for all of your patients.
00:20:22
Speaker
And I think that clinical pharmacists understand that.
00:20:26
Speaker
I think you have to just walk them through it and then make sure you don't blow up the bank when you do this, right?
00:20:32
Speaker
I think if you do that, you get access to things that you need for your patients.
00:20:38
Speaker
And I absolutely agree.
00:20:38
Speaker
And I think that with healthcare moving to value-based healthcare, obviously,
00:20:43
Speaker
I think as clinicians, we are responsible to some extent to being told what to do because we didn't take responsibility when we had the chance.
00:20:52
Speaker
And I think in critical care, multiple examples.
00:20:56
Speaker
And I think the example that would apply to angiotensin 2 is that right now, if you have a patient who might have pneumonia and who's getting fluids and needs maybe a little bit of vasopressor to get them through the next couple of hours, it's not the patient in whom you're going to start angiotensin 2.
00:21:12
Speaker
And I think that you're right.
00:21:14
Speaker
We need to understand that.
00:21:15
Speaker
But also, like you said, I appreciate that you share with us numbers so that our clinicians can start really thinking about in terms of very practical terms, what it means from a cost benefit ratio and what are the right patients pairing that in terms of value, but also with the evidence that we have, which I think is very important.
00:21:33
Speaker
And we need to take responsibility for the cost part of value, which we haven't been as good, I think, as clinicians in the past.
00:21:41
Speaker
Yeah, I think that one place where we have been
00:21:44
Speaker
able to demonstrate this value is with the use of vasopressin.
00:21:48
Speaker
So vasopressin is a drug which when it works, it works really well.
00:21:54
Speaker
But oftentimes it doesn't do anything.
00:21:57
Speaker
So if you had asked me, oh, I don't know, two years ago and said, hey, Mink, what's vasopressin like in your clinical practice?
00:22:05
Speaker
I would have told you that a third of the time it's really extraordinary.
00:22:08
Speaker
It gives me rapid effective catecholamine sparing.
00:22:11
Speaker
And I often can stop
00:22:13
Speaker
stomping up my norepinephrine.
00:22:15
Speaker
And those of us who take care of these patients know that catecholamines have real toxicity.
00:22:21
Speaker
They're immunosuppressive.
00:22:23
Speaker
They cause mardicardial damage at high concentration, and they cause capillary derecruitment.
00:22:28
Speaker
So being on high doses of catecholamines, like everyone knows, is not good for you.
00:22:32
Speaker
So I use a lot of vasopressin in my clinical practice.
00:22:34
Speaker
A third of the time, I would give vasopressin and be like, eh, meh, you really do that much for me.
00:22:39
Speaker
And a third of the time, it does absolutely nothing.
00:22:43
Speaker
Now, what has been now since been shown is the Satcha paper, which was published, I think, in 2018.
00:22:49
Speaker
It was on the Cleveland Clinic.
00:22:52
Speaker
And what they basically did is they looked at blood pressure response to this to vasopressin.
00:22:58
Speaker
And what they found is that half the time, around 45% of the time, if you get vasopressin, you get a nice clinical response.
00:23:04
Speaker
And either the catecholamines go down or you get a nice blood pressure effect of both.
00:23:08
Speaker
And half the time, nothing happens.
00:23:10
Speaker
And when I mean nothing, I mean nothing.
00:23:13
Speaker
And that mirrors most people's clinical experience.
00:23:16
Speaker
But if you ask any intensivist, what do you do once you've started vasopressin and it doesn't work?
00:23:22
Speaker
The answer, including myself, is the same.
00:23:24
Speaker
I keep it going.
00:23:27
Speaker
So when vasopressin was very cheap, that probably wasn't a big deal.
00:23:31
Speaker
The vasopressin is quite expensive.
00:23:33
Speaker
It's around $500 a day.
00:23:35
Speaker
So if you look at vasopressin costs, leaving it on when it's not working,
00:23:40
Speaker
generally costs per patient somewhere between $3,000 and $6,000 per patient.
00:23:45
Speaker
So you've got nothing for it and you keep it on.
00:23:48
Speaker
If you had a patient with a cardiac index of 1.8 and you put dobutamine on and the index didn't go up, none of us would keep it on.
00:23:58
Speaker
But we don't do that with vasopressin.
00:24:00
Speaker
And so what many centers have done is they've become much more disciplined about stopping the vasopressin when it doesn't work.
00:24:10
Speaker
And when they do that, they're able to open up a fair amount of currency in their pharmacy budget to make room to have all the tools in the toolbox.
00:24:20
Speaker
I think that's a very logical approach, which doesn't change the way you take care of patients, but expands your options.
00:24:28
Speaker
Yeah.
00:24:29
Speaker
And I think that's something that we've talked about before, but also I think just from a very coherent therapeutic approach is something that I never understand is
00:24:39
Speaker
If you already are on a catecholamine and you're having trouble, why are you adding a third, a fourth catecholamine before trying a different agent and a different pathway?
00:24:50
Speaker
Yeah, so that drives me crazy, right?
00:24:51
Speaker
So people have forgotten what they learned in their first year of medical school, that dopamine is converted to norepinephrine, which is converted to epinephrine in your body.
00:25:01
Speaker
And so when I'm on high-dose norepinephrine and the vasopressin isn't working and my genius fellow shows up and goes, oh, let's try epi.
00:25:09
Speaker
I'm like, oh, why didn't I think of that?
00:25:11
Speaker
I mean, do you really think that this is the answer?
00:25:15
Speaker
I mean, you're already on 50 of Levo.
00:25:18
Speaker
You're on vasopressin.
00:25:20
Speaker
I mean, do you think there's an alpha receptor in the amygdala that's in witness protection that you're going to find with this epinephrine and save them?
00:25:27
Speaker
I find it incredulous, this behavior.
00:25:31
Speaker
And then people will argue with, oh, phenylephrine can rescue.
00:25:33
Speaker
I'm like,
00:25:34
Speaker
Which new alpha receptor is involved?
00:25:36
Speaker
I mean, have I missed something in medical school?
00:25:39
Speaker
I really find it to be preposterous.
00:25:41
Speaker
I think it's the French actually have it right.
00:25:45
Speaker
They use norepinephrine for everything.
00:25:47
Speaker
They don't have vasopressin.
00:25:49
Speaker
They don't add epi.
00:25:49
Speaker
They don't add dopamine.
00:25:51
Speaker
They don't add anything.
00:25:52
Speaker
They are firm believers in norepi only.
00:25:55
Speaker
Now, I think that's got some serious problems to it, obviously, but I give them credit for being purists.
00:26:01
Speaker
And
00:26:02
Speaker
And Mink, is there any evidence or any suggestion that those patients in whom vasopressin does nothing would be exactly those patients in whom the ANG1 and ANG2 ratios are totally off?
00:26:16
Speaker
So we don't have that data because we don't have is people having had that sort of vasopressin challenge and then at that moment having an ANG1-ANG2 ratio.
00:26:27
Speaker
And that's a study which I hope we get to do soon.
00:26:31
Speaker
But one of the things that was really interesting is if you look at the Satcha paper and you look at the vasopressin responders, meaning people who have a blood pressure effect, they have a survival of around 50%.
00:26:45
Speaker
If you look at the people who don't respond to vasopressin, only 25% of those folks live.
00:26:52
Speaker
So vasopressin responders do better than vasopressin non-responders.
00:26:57
Speaker
And if you think about norepinephrine,
00:26:59
Speaker
That's also the case.
00:27:00
Speaker
All of us have gone to the ER.
00:27:01
Speaker
You see a super toxic patient.
00:27:03
Speaker
They get their fluids.
00:27:04
Speaker
Get them upstairs.
00:27:05
Speaker
You get a central line in, and you put them on a little bit of norepinephrine, and they do great.
00:27:10
Speaker
They completely settle out, and they're on 5, 10,.05, or.1 of norepi.
00:27:17
Speaker
They settle down.
00:27:18
Speaker
You sort them out.
00:27:20
Speaker
They're at a bioturine, and they get better.
00:27:22
Speaker
And there's another group of patients who looks very much the same at the beginning, and you give them norepinephrine, they just laugh at it.
00:27:29
Speaker
And then suddenly you're on 50 Alevo and you're like, God, this person's so different.
00:27:33
Speaker
But in my mind, I thought that looks a lot like antibiotic sensitivities.
00:27:40
Speaker
And if you look at the angiotensin 2 data, it's exactly the same.
00:27:44
Speaker
So if you get angiotensin 2 and you have a blood pressure response, you have a survival of 30, of 70%.
00:27:52
Speaker
So if you get angiotensin 2 and you survive, and you have a blood pressure response, your survival is, is phenomenal.
00:27:58
Speaker
right?
00:27:59
Speaker
70% survival.
00:28:01
Speaker
If you don't respond, it's the opposite.
00:28:04
Speaker
You have a 70%, I'm sorry, 30% survival, right?
00:28:09
Speaker
So basically it's this huge delta.
00:28:11
Speaker
So I said to myself, you know what, this is an approach that we should apply.
00:28:17
Speaker
And we coined this idea, which we published in critical care, which is broad spectrum vasopressors.
00:28:22
Speaker
So I don't think this will happen now because vasopressin is more expensive than norepinephrine.
00:28:27
Speaker
And angiotensinase 2 is more expensive than vasopressin on a per day basis.
00:28:33
Speaker
But I think in the future, Sergio, in addition to getting your lactate and your blood cultures, you're going to get a vasopressin sensitivity panel and you're going to start all three.
00:28:43
Speaker
Because time to your sensitive vasopressor is going to be life-saving.
00:28:49
Speaker
But I also think that the advantage that you have with respect to making the analogy of the broad spectrum antibiotics, broad spectrum
00:28:57
Speaker
base suppressors would be that you will see a response much quicker than with antibiotics.
00:29:02
Speaker
So I think that maybe the lesson for now is that if you start escalating or things are not working, to move through the agents a lot quicker than on day five.
00:29:13
Speaker
Oh, I agree with that.
00:29:14
Speaker
And I mean, I think that if you've taken nothing away else from this podcast, the one thing I will say is that
00:29:22
Speaker
what Sergio just said is critically important.
00:29:24
Speaker
If you're waiting until day five of shock to add whatever agent, it doesn't matter because neither vasopressin nor angiotensin 2 are palliative care drugs.
00:29:34
Speaker
If it's the last drug you put on before the morphine drip, you've not done anyone any favors.
00:29:39
Speaker
If you're failing, try something else, right?
00:29:43
Speaker
I think that is a super important recommendation.
00:29:47
Speaker
If you have waited until 50 of Levo,
00:29:50
Speaker
to go to your non-catecholamine vasopressor, whether it be vasopressor or ang2, I really think you're not treating the patient well.
00:29:58
Speaker
This is my opinion, but you are late.
00:30:02
Speaker
This patient is catecholamine resistant.
00:30:05
Speaker
And if they're going to be sensitive to another vasopressor, you better put it on before you lose the ability to do anything.
00:30:13
Speaker
And I wanted to maybe review just some practical issues in terms of
00:30:18
Speaker
at the bedside dosing and let's say that you're gonna pull the trigger and you're gonna start angst two, how you would do it and just give us a little bit of a walk through that very quickly.
00:30:30
Speaker
Yeah, so I think that you have to decide if you, how much you hate catecholamines.
00:30:35
Speaker
So I'll give you two approaches that I've seen used and I'll tell you the one that I use.
00:30:41
Speaker
So if you, the standard approach, let me start with that, is start with 20 nanograms per kg per minute.
00:30:49
Speaker
And what you ought to see is a MAP response, and that should allow you to start coming down off your catecholamines.
00:30:58
Speaker
And what I do in my clinical practice, I'll speak for myself now, is when I put ANG2 on, my goal is to get the catecholamines out of the toxic range.
00:31:08
Speaker
So if they're on some insane cocktail of phenylephrine, epinephrine, and norepinephrine, which I see from time to time,
00:31:16
Speaker
The first thing I get rid of is the phenylephrine because it's mostly useless.
00:31:20
Speaker
Then I get the epi off, and then I move the norepi down to 0.1 or under.
00:31:26
Speaker
And in my clinical practice, I will get the ang2 up to 40 nanograms per kg per minute in order to do that because I think catecholamine toxicity is very real and very problematic.
00:31:39
Speaker
If you take the time to read the norepinephrine label, you'll see it actually can cause acute kidney injury.
00:31:44
Speaker
and it causes capillary derecruitment, and we all know what it does to digits and perfusion.
00:31:49
Speaker
And then what I typically do is, if I can get them into that sweet spot, I'll try and hold that position and not give them any more volume, because most of these folks are typically volume overloaded already, to some degree.
00:32:04
Speaker
And then if they're on CRRT and we can start pulling volume safely, I'll do that.
00:32:10
Speaker
But I'll certainly try and avoid
00:32:13
Speaker
making them more volume overloaded because I find saltwater drownings to be very common in North American ICUs.
00:32:19
Speaker
And I think we use way too much crystalloid.
00:32:23
Speaker
And then I usually then bring the vasopressors down in parallel.
00:32:27
Speaker
I'll usually get rid of the vasopressin thereafter.
00:32:30
Speaker
And then depending on what the patient's doing clinically, I'll pull off the norepinephrine and NG2 and
00:32:36
Speaker
If there's an opportunity to do it when an ANG2 bag is empty and we don't have to use a new vial in order to be prudent with cost, I'll usually then try and get the ANG2 off in anticipation of that.
00:32:46
Speaker
That's sort of the standard approach.
00:32:49
Speaker
And can I ask you two more questions and a little more granular?
00:32:52
Speaker
When you go from 20 to 40, what increments are you using?
00:32:56
Speaker
I usually go by 10 because if there are a lot of catecholamine, the goal is to get them out of the catecholamine toxic range.
00:33:04
Speaker
Okay.
00:33:05
Speaker
And the other question I was going to ask you is those in the studies from ATHOS3, the super responders were patients in whom you very quickly had to go down on the dose, right?
00:33:15
Speaker
And ended up like on less than five nanograms.
00:33:18
Speaker
Is that what you define as super responders?
00:33:21
Speaker
Yeah.
00:33:21
Speaker
So that data was just published in Annals of Intensive Care Medicine.
00:33:24
Speaker
And there is this subgroup of patients that are exquisitely sensitive to angiotensin II.
00:33:29
Speaker
And when you run into that group, it becomes pretty self-evident because, you
00:33:33
Speaker
you start having to take off vasopressors very, very rapidly.
00:33:37
Speaker
And what I would say is if you are in that pleasant scenario, there will be a little bit of action at the bedside because these patients can have transient hypertension, especially in the label.
00:33:47
Speaker
And then the goal is to basically, you may have to back off a little faster than you're normally used to, but it's very important that if you're going to be doing that, you need to be at the bedside.
00:33:57
Speaker
And you start taking things off as appropriate and reach back down to your target map.
00:34:01
Speaker
And in that scenario, similarly, I try and get all the vasopressors down to lower doses and leverage synergy.
00:34:10
Speaker
And what about the other question I was going to ask you in terms of dosing is, is there a max dose?
00:34:17
Speaker
You talked about 40, but is there value in going above that?
00:34:21
Speaker
So the people, and I have a few colleagues of mine, not many, they follow the label of
00:34:28
Speaker
extremely tightly to get maximum catecholamine sparing.
00:34:32
Speaker
So a few colleagues of mine, when they put ANG2 on, they go, they start at 20, but they will move up to 80 as quickly as they can safely.
00:34:42
Speaker
And in a way that's appropriate to get as much catecholamine off as possible.
00:34:48
Speaker
And they actually try and push the catecholamine dose to off because they're, they're very anti-catecholamine.
00:34:54
Speaker
You typically see this in heart surgeons.
00:34:57
Speaker
because cardiac surgeons despise catecholamines.
00:35:01
Speaker
Low-dose epi is a little bit different, but they don't like norepinephrine because of the problems it causes with pulmonary hypertension, the issues they tend to have with, you know, AFib and AFlutter and tachyarrhythmias.
00:35:14
Speaker
And so we've seen an enormous amount of use of ANG2 in post-cardic surgery-based apeligia, where it's performed extremely well, and there's this very anti-catecholamine bias to start.
00:35:25
Speaker
And what they do is they go up to 80 if they need it.
00:35:29
Speaker
They get the catecholamines down.
00:35:30
Speaker
And then by hour three, they make sure they're down to 40, you know, because they want to stay within the label.
00:35:37
Speaker
And I would say that the doses that we have studied that go out beyond three hours is 40.
00:35:44
Speaker
And I think that that's where we have the best known safety and people ought not to go above 40, you know, unless there's some extraordinary event that I haven't considered.
00:35:54
Speaker
but 40 ought to be the top dose.
00:35:56
Speaker
And we talked about the safety profile earlier, and obviously in general in ATHOS and ATHOS-3, the safety profile was excellent.
00:36:04
Speaker
But what are the complications that the clinician should be worried about or aware of based on what we know so far?
00:36:10
Speaker
Yeah, so that's an important question.
00:36:11
Speaker
I'm glad you asked it.
00:36:13
Speaker
And so what we saw in ATHOS-3 is that there was an imbalance and a higher number of
00:36:21
Speaker
VTE events, thromboembolic events in the angiotensin II arm of low grade.
00:36:27
Speaker
So, and that's why in the label, and we had this discussion with FDA, the key was to make sure that patients who are getting angiotensin II are on appropriate VTE prophylaxis.
00:36:39
Speaker
And obviously they're fully anticoagulated.
00:36:41
Speaker
You're probably in decent shape, but VTE prophylaxis is something that patients ought to be on before getting angiotensin II based on what we saw in the trial.
00:36:49
Speaker
And most of the events that did occur were mild in nature, but there was a numerical asymmetry.
00:36:55
Speaker
I think it's important that people be mindful of that.
00:37:00
Speaker
And I guess other complications would be related just, I mean, to the effects of the drug, such as hypertension and making sure that, I mean, especially those super responders, that you're titrating that adequately so you don't have these overshooting of blood pressures that could be dangerous in some patients.
00:37:15
Speaker
Yeah, I think that's right.
00:37:16
Speaker
I think that people should just keep in mind that angiotensin II has a half-life of 30 seconds.
00:37:21
Speaker
And so if you're in a scenario where you walk into a room and you have a patient who's hypertensive and they're on angiotensin II, instead of trying to turn things down very quickly, I think the easiest thing to do is just to pause the angiotensin II.
00:37:34
Speaker
Don't turn it off.
00:37:35
Speaker
Just go to the IV pump and hit pause.
00:37:38
Speaker
And because of the half-life is in 30 seconds, within 60 seconds, the angiotensin II effect will begin to drop off.
00:37:44
Speaker
And then you can find a new dose with whichever cocktail of vasopressors you're on to get you into a place without turning things off too rapidly and then risking, you know, a big seesaw, which all of us want to try and avoid.
00:37:56
Speaker
So the nice thing about Edge 2 is on-off because it's very short half-life.
00:38:01
Speaker
So you can take advantage of that without having to DC it and restart it.
00:38:05
Speaker
Just hold it.
00:38:07
Speaker
And, you know, at the bedside, it's a very nice way of getting immediate control.
00:38:11
Speaker
and preventing your nurse from wanting to assassinate you in real time.
00:38:16
Speaker
Because this is not a thing that makes your ICU nurse happy.
00:38:19
Speaker
They don't like a lot of variability in their life, especially if you're causing it.
00:38:25
Speaker
And you did mention cardiothoracic surgeons and post-operative vasoplegium patients who underwent the cardiopulmonary bypass or CT surgery.
00:38:35
Speaker
So I understand that in ATHOS III, 6% or so of the patients
00:38:40
Speaker
were this type of shock, so not a very big number.
00:38:42
Speaker
The majority were septic shock.
00:38:44
Speaker
But what have we learned since then, and what has been the experience in the field with using ANG2 for these patients?
00:38:51
Speaker
Yeah, that's a great question, and I have to say that I massively underestimated this group of patients and the unmet need.
00:38:58
Speaker
So Andy Shaw, who's a good friend of mine, who's chair of anesthesia up in Edmonton, who was previously at Vanderbilt,
00:39:05
Speaker
know what when the at this data first came out you know he said to me like how come you guys didn't enroll more vasoplegia patients in the trial i said you know i don't know any people enrolled what they enrolled he said bink he said let me tell you what my day is every day i go in to a patient's room in the pre-operative scenario and i consent them for cardiac anesthesia for cardiac pulmonary bypass surgery and invariably they've taken an ace inhibitor that morning and then
00:39:32
Speaker
I put them on a cardiopulmonary bypass where I bypass their heart and lung anyway from 90 minutes to three plus hours.
00:39:39
Speaker
And you've already told me that Ang1 gets converted to Ang2 in the lung, which means that for that whole procedure, they're not really converting their Ang1 to Ang2 and they took an ACE inhibitor or an ARB.
00:39:49
Speaker
So now I'm stunned at the end of the case that there are high dose catecholomies.
00:39:55
Speaker
So, you know, it was so obvious.
00:39:57
Speaker
I was really quite embarrassed actually.
00:39:59
Speaker
And, you know,
00:40:00
Speaker
You know, as soon as the trial was done, we're like, okay, we have a vasoplegia trial.
00:40:04
Speaker
We're actually working with some investigators to do that.
00:40:08
Speaker
But, you know, cardiac surgeons don't wait.
00:40:10
Speaker
You know, they get graded on their scores.
00:40:12
Speaker
AKI matters to them.
00:40:13
Speaker
Getting them off the vent is faster.
00:40:14
Speaker
So very big centers have already started and using ASH2 in their post-op surgery vasoplegia cases.
00:40:21
Speaker
And Mayo Clinic, not surprisingly, has been out the gate first.
00:40:25
Speaker
They've actually published a case series of four patients.
00:40:29
Speaker
And actually a second one that was a solo one on a patient with a heart transplant.
00:40:33
Speaker
And they have shown really nice results.
00:40:35
Speaker
There's some other case series that are out.
00:40:39
Speaker
I think it's incumbent on us here to try and get an RCT out the door.
00:40:43
Speaker
But I think that hard for us is the cardiac surgery world is already using this so much and they already see value in it that
00:40:53
Speaker
I kind of don't know what the new baseline is for them.
00:40:55
Speaker
And when we're designing a study, we designed a study where we thought, hey, let's use ANG2 versus methylene blue.
00:41:02
Speaker
And I was informed by this site that we were going to do this study.
00:41:04
Speaker
And they're like, look, we've already moved ANG2 before methylene blue.
00:41:07
Speaker
Methylene blue doesn't do anything for us.
00:41:09
Speaker
B12 is useless.
00:41:10
Speaker
This works much better.
00:41:11
Speaker
We're getting much better results.
00:41:13
Speaker
And so this is a good problem to have, but mechanistically, it makes a lot of sense as to why these patients have problems.
00:41:21
Speaker
And I think what's interesting is
00:41:23
Speaker
I was worried about A2 blockers and ANG2 not working in them.
00:41:28
Speaker
And because these patients are often taking A2 blockers the day before the day of surgery, we have found based on the experience that these patients still respond very well to ANG2, but they just need a slightly higher dose.
00:41:41
Speaker
And I think that also it's important, I mean, for the audience to understand that, again, we're not saying that this would be the first line vasopressor
00:41:50
Speaker
for patients post-cardiopulmonary bypass and cardiopulmonary surgery.
00:41:54
Speaker
But clearly, I would argue that with the ATHOS-3 enrollment, the case studies, there's already more evidence than for methylene blue, which a lot of people have used in their practice over the years.
00:42:07
Speaker
So clearly, I mean, there's a role in getting to this drug very quickly is probably important.
00:42:13
Speaker
And like you said, I mean, it's approved for this type of shock.
00:42:18
Speaker
That's right.
00:42:18
Speaker
So that is, it is a form of distributive shock vasoplegia.
00:42:22
Speaker
So it's an on-label indication.
00:42:24
Speaker
And, you know, I've used methylene blue from time to time in my career, but I mean, I think the big concern about methylene blue, particularly in postpartic surgery patients at high dose, it could actually cause vasoconstriction because it's soaks up too much nitric oxide too fast in certain vascular beds.
00:42:38
Speaker
And so it's not sort of this idea that
00:42:41
Speaker
of, you know, well, what harm could it do?
00:42:43
Speaker
It could actually do some real harm.
00:42:45
Speaker
And, you know, we've also seen things like this with this whole IV vitamin C business.
00:42:49
Speaker
A colleague of mine was visiting a group up in the Midwest and they were giving high-dose vitamin C for vasoplegia and they got some very beautiful ATN from it, which is a known complication of vitamin C. And so I think that these rescue therapies, you feel like, hey, what could happen?
00:43:04
Speaker
I'm desperate.
00:43:05
Speaker
And I understand that.
00:43:06
Speaker
That makes sense.
00:43:07
Speaker
We've all been there.
00:43:09
Speaker
My feeling is use something which has been shown in a randomized controlled trial.
00:43:12
Speaker
The safety profile you understand is titratable and it has a short half-life.
00:43:18
Speaker
So if it isn't doing what you want it to do, it goes away.
00:43:21
Speaker
Yeah.
00:43:23
Speaker
And I think that clearly, I mean, like you said, the surgeons are going to embrace this probably a lot quicker just because they live and die on those results.
00:43:32
Speaker
And they're going to be very interested in making sure that they have the right drugs as soon as possible.
00:43:37
Speaker
So on the same note, Mink, I know that in ATHOS3, there was not any ECMO patients, but I have seen some reports of use of angiotensin II in ECMO patients.
00:43:48
Speaker
Any comments in this particular population?
00:43:51
Speaker
Yeah, so that's a great question.
00:43:53
Speaker
So in ATHOS3, there were some ECMO patients.
00:43:55
Speaker
VA ECMO was excluded, but VV ECMO was allowed in.
00:43:58
Speaker
There was a handful of patients.
00:44:00
Speaker
And Marlise Osterman and a few others have published a case series on that.
00:44:05
Speaker
And what we've seen is some very nice results in ECMO.
00:44:08
Speaker
You know, I think one of the things which is very interesting is that if you're on ECMO and you have this profound lung injury because of VV, you know, and we have not specifically looked at this.
00:44:18
Speaker
But one of the things I really want to look at is do these patients have the angio-1, angio-2 ratio business that we're concerned about?
00:44:24
Speaker
Because if they have lung injury or you're bypassing their lungs in VA ECMO, are they able to produce angiotensin too?
00:44:31
Speaker
And I think increasingly the answer appears to be that there is some disorder there.
00:44:35
Speaker
And we have some very nice case series already published showing really dramatic rescues in patients.
00:44:40
Speaker
Patients coming off of CRT as well in ECMO, we're not having to go on when they're about to go on.
00:44:46
Speaker
And so I think that in those patients in particular where you're sort of in for a penny, in for a pound, you've already invested so much in them, we've seen some really dramatic saves, which has obviously been very pleasing.
00:44:57
Speaker
I think the hard part with ECMO, as you know, is patient selection is so critical.
00:45:02
Speaker
in what the results are going to be.
00:45:04
Speaker
But if you are investing in someone, particularly a young flu patient who crashed the ECMO, we've seen some extraordinary saves with ANG2.
00:45:13
Speaker
And so this has been something which we've been really pleased about.
00:45:16
Speaker
And my big complaint are my colleagues who have these cases who will not publish them fast enough.
00:45:22
Speaker
So those of you who are listening to this, you know who you are.
00:45:26
Speaker
Please put the pen to the papyrus as soon as you can.
00:45:30
Speaker
Excellent.
00:45:31
Speaker
So I think that this would be a good time to maybe summarize where you see the state of ANCH2 in 2019 in terms of what are the indications, where does it fall in our list, and what should clinicians, I mean, think about when they're trying to either utilize this or bring this to their practices?
00:45:52
Speaker
Yeah.
00:45:52
Speaker
So I think that's a good place to start and sort of look at a summary.
00:45:55
Speaker
And I would say that
00:45:57
Speaker
The summary is as follows.
00:45:59
Speaker
We have been out one year and we have seen no new safety issues and we have seen a drug which performs as advertised.
00:46:08
Speaker
It has an expense associated with it that every healthcare provider along with their institution will have to navigate.
00:46:15
Speaker
I'm obviously super biased on this, but I think you have to have this tool in your toolbox.
00:46:20
Speaker
I think there are ways to have conversations with your pharmacy to do it.
00:46:23
Speaker
From a pure value standpoint,
00:46:26
Speaker
If you want to place the drug in the place where you get the most survival value and cost value, you do that by using it in patients with acute kidney injury because those are the patients who have the most disordered ANG1 to ANG2 ratio.
00:46:41
Speaker
I also think that because we've just achieved European approval, the CHMP just recommended approval in Europe, I think that there'll be a lot of data generated in Europe in the next 12 to 18 months
00:46:55
Speaker
And so I look forward to what those data do to inform global practice of angiotensin 2.
00:47:02
Speaker
And I would say that the other big thing that I think we need to do here at La Jolla is find a better way to inform the clinician of what that angio-1, angio-2 ratio is.
00:47:15
Speaker
I think we are frankly on the cusp of personalized shock care.
00:47:21
Speaker
And I think that if we can find a way
00:47:24
Speaker
to find a biomarker that tells you what the angio-angio-angio-2 ratio is.
00:47:29
Speaker
You can identify that patient appropriately and in a timely fashion.
00:47:33
Speaker
It can't be a send out that comes back a month later.
00:47:36
Speaker
And that's the problem with the angio-angio-angio-2 assays.
00:47:39
Speaker
These are very specialized assays because they're small peptides and they degrade very rapidly.
00:47:44
Speaker
So we're working very hard here to find that marker to get out to the bedside.
00:47:50
Speaker
But I think in 2019,
00:47:53
Speaker
I think we have a really good sense that we have a really nice tool in the toolbox.
00:47:57
Speaker
And in that AKI place is where you get not just clinical value and preventing patients and getting them off of dialysis fast, which is, of course, good for them and probably good for them downstream from CKD and ESRD issues.
00:48:10
Speaker
But it actually saves hospitals money.
00:48:13
Speaker
And there's a lot of big health care systems that are putting Ang2 on, and they're going to do economic analyses on this.
00:48:19
Speaker
And we look forward to those data coming out as well.
00:48:22
Speaker
And I would add, Mink, that for clinicians who are trying to get this on board, A, use it judiciously.
00:48:30
Speaker
I mean, as you said, I mean, it's not a drug that you're just going to start giving everybody who's hypotensive, but use it the right way.
00:48:36
Speaker
But also I think that using your CT surgeons as allies is always a good strategy to get things on the PNT, because if you can add drugs that have been studied, that are safe, that you can use in that particular population,
00:48:51
Speaker
I think that the hospital is always happy to help their CT surgery programs flourish.
00:48:57
Speaker
Yeah, I think that's right.
00:48:58
Speaker
And I think that if you're going to have success with a pharmacy that's very cost sensitive, you need a coalition.
00:49:04
Speaker
You need not just one person who's really lathered about this.
00:49:07
Speaker
I think you need to get a bunch of people.
00:49:10
Speaker
And I think it's really important that you engage your clinical pharmacists.
00:49:13
Speaker
You know, the clinical pharmacists are at the bedside with you helping us dose the drugs appropriately.
00:49:18
Speaker
And this is an opportunity for them to help
00:49:21
Speaker
offer a nice way to use the drug appropriately to help get outcomes.
00:49:27
Speaker
My one ask is please do not give the drug to dead people.
00:49:32
Speaker
This is drugs trade name is Geopreza, not Liquid Jesus.
00:49:36
Speaker
This does not bring people back from the dead.
00:49:40
Speaker
If you are on a knocker silly high dose of catecholamines and you use this and then you turn around and say it didn't work, I would argue to you that you are too late.
00:49:50
Speaker
You cannot bring cells back from cell death.
00:49:54
Speaker
So if you're going to show value, you have to use it thoughtfully and early, not first line, but second line or third line appropriately, and you will see extraordinary results.
00:50:08
Speaker
If you wait until they're dead, nothing works.
00:50:12
Speaker
And I think that's a great place to stop the discussion.
00:50:16
Speaker
I definitely look forward, Minka, to learning more about
00:50:20
Speaker
how we can personalize vasopressor therapy, and I hope that we'll have some emerging data over the next 12 months that will be exciting.
00:50:28
Speaker
You've been on the podcast before, so you know how this usually ends.
00:50:31
Speaker
I'll ask you a couple of questions if that's okay with you that are not related to vasopressors.
00:50:37
Speaker
Of course.
00:50:38
Speaker
So we talked about books last time, and this time what I wanted to know is if you were stuck somewhere and could only have one album, what would it be in terms of music?
00:50:50
Speaker
it'd probably be Pink Floyd, Dark Side of the Moon, or Wish You Were Here, but one of the two.
00:50:57
Speaker
I'll tell you a sort of funny story about Wish You Were Here, the song from the Pink Floyd.
00:51:02
Speaker
So my middle daughters are on 11, and we're in my car, and we're driving, and I said, hey, listen to this song and tell me what you think.
00:51:09
Speaker
And my daughters are not really into my music, but, you know, she listened to the entirety of the song, and I thought, wow, just, you know, this is surprising.
00:51:18
Speaker
She didn't just,
00:51:19
Speaker
start complaining after the first 60 seconds and get rid of it.
00:51:22
Speaker
And I said, what did you think?
00:51:24
Speaker
And she said, well, it's not bad, dad.
00:51:26
Speaker
It's only one instrument.
00:51:28
Speaker
And, you know, if I had a little more oots, oots, oots in it, it would have been much better.
00:51:32
Speaker
And, you know, the New Jersey side of me was about to strangle her.
00:51:37
Speaker
I'm like, it is a classic.
00:51:39
Speaker
What are you talking about?
00:51:40
Speaker
But I decompressed because I did ask her her opinion.
00:51:44
Speaker
It wasn't the opinion I was hoping for.
00:51:47
Speaker
And so, yes, it would be one of those two Pink Floyd albums.
00:51:50
Speaker
And if my dog was with me, she'd probably kill me because she doesn't care for Pink Floyd.
00:51:54
Speaker
But maybe in a couple of years, she'd be able to reevaluate that position and appreciate it.
00:52:00
Speaker
I agree.
00:52:00
Speaker
I think she'll eat her broccoli before she listens to Pink Floyd, but that's a separate issue altogether.
00:52:06
Speaker
Excellent.
00:52:07
Speaker
My second question relates to failure.
00:52:10
Speaker
I think that in this culture, people seem to really think failure is not an option.
00:52:15
Speaker
that I believe that failure should be embraced.
00:52:17
Speaker
I mean, it's the best teacher we have.
00:52:19
Speaker
So I wanted to ask you, Mink, if you could share with us a really good failure, one that really taught you something valuable.
00:52:26
Speaker
Well, I will tell you that the story of angiotensin 2 is mostly failure with some extraordinary successes in between.
00:52:34
Speaker
You know, when I first set out to work on angiotensin 2, everyone said to me, well, it was such a good idea to have been done before.
00:52:41
Speaker
And you can't get this to work by yourself.
00:52:44
Speaker
An individual cannot.
00:52:45
Speaker
make this happen.
00:52:46
Speaker
It's a generic drug.
00:52:47
Speaker
It's well known.
00:52:48
Speaker
You can't get IP around it.
00:52:50
Speaker
And, you know, I think maybe I was just too stupid or too stubborn, but, you know, from the point of the pilot trial to actually getting at this trip and running, you know, when we tell the story, it sounds also seamless and it sounds like everything comes together.
00:53:06
Speaker
I think I called something in the vicinity of 35 drug companies.
00:53:11
Speaker
Um,
00:53:12
Speaker
I spoke to all kinds of people and everywhere I went, it failed, it didn't work, I couldn't get it to go.
00:53:18
Speaker
And I think that if you, my take home message is it's not just about failure because we're all going to fail, but I think it's about perseverance.
00:53:27
Speaker
So I think, you know, this is kind of obvious.
00:53:30
Speaker
I don't think anyone is so stunned that angiotensin 2 helps.
00:53:34
Speaker
I think we're learning these interesting things about
00:53:37
Speaker
ACE defect, which we didn't know.
00:53:39
Speaker
And so we have some nice science, which we learned along the way and it's helping patients.
00:53:42
Speaker
But this had been out for 40 years and clinicians used it.
00:53:45
Speaker
We just forgot about it.
00:53:46
Speaker
But if you believe in something, it's about grit.
00:53:50
Speaker
It's about your passion and your perseverance, which means you're going to feel a lot along the way.
00:53:56
Speaker
And the key is to pick yourself up and try again.
00:54:01
Speaker
And if you don't do that and
00:54:03
Speaker
There isn't a person I know who hasn't done an extraordinary thing, who hasn't had many failures along the way.
00:54:10
Speaker
And I think it's the best teacher.
00:54:12
Speaker
I completely agree with that assessment.
00:54:14
Speaker
And it's interesting that you mentioned specifically to Andrew Tencent too.
00:54:18
Speaker
There's a book that came out this year called Loonshots by Safi Bakal.
00:54:23
Speaker
I don't know if you had a chance to read it, but basically... No, no, please send me the link.
00:54:27
Speaker
I'd love to hear about that.
00:54:29
Speaker
I'll link it in the show notes, but I think you will love it because basically...
00:54:32
Speaker
They go through the history of several drugs and the whole premise is that a drug is killed four times before it succeeds.
00:54:41
Speaker
So clearly this is not unique to angiotensin II, but I think that you will find this read particularly interesting, Mink.
00:54:50
Speaker
So I definitely, I mean, we'll share with you that link, but also put it in the podcast links.
00:54:55
Speaker
And- Oh, that'd be great.
00:54:57
Speaker
The last question would be just to close.
00:55:00
Speaker
Is there anything in particular you would like every listener to think about or know after this episode?
00:55:06
Speaker
Yeah, and I'm going to say this now as a clinician, as someone who's had the opportunity to use angiotensin II at the bedside.
00:55:12
Speaker
And, you know, I've seen around 380-ish people die in my clinical career.
00:55:20
Speaker
It's a little bit morbid that I kind of keep track of this number.
00:55:22
Speaker
I don't have it down to the exact number, but I have within around 10.
00:55:26
Speaker
And about half of those are
00:55:28
Speaker
miserable codes and terribleness that you inherit.
00:55:31
Speaker
But the other 200 or so are refractory-based adulatory shock.
00:55:35
Speaker
They just outrun you and you're like, this is not going anywhere.
00:55:39
Speaker
They're on some obnoxious amount of norepinephrine.
00:55:41
Speaker
You know they're going to die.
00:55:41
Speaker
You go to the family, you tell them they're going to die.
00:55:45
Speaker
And, you know, we all do it.
00:55:46
Speaker
We've all been there.
00:55:47
Speaker
It's annoying.
00:55:48
Speaker
It really is unpleasant to have to go and do this business of telling a family member that their loved one is dead.
00:55:54
Speaker
And we've all had to do this and it sucks.
00:55:56
Speaker
And I think the single most important thing that has kept me sane through this, aside from scotch, is you feel like I've done everything I know how to do.
00:56:07
Speaker
I did source control.
00:56:08
Speaker
I optimized the resuscitation.
00:56:09
Speaker
I did everything in a timely fashion.
00:56:11
Speaker
We looked everywhere.
00:56:12
Speaker
And you drive home and you're still a little bit sick about it, but you're like, I did everything that I could, and that makes you feel good.
00:56:20
Speaker
And I'm not saying this as the person who's done a lot of the science in the answer, so I'm telling you this as a clinician.
00:56:26
Speaker
If you think you've done everything and you haven't tried ANG2 in the correct patient, you're wrong.
00:56:34
Speaker
And this is a personal level conversation.
00:56:37
Speaker
And anyone can call me out and say, you're full of it, Mink, and I'm okay with that.
00:56:41
Speaker
I'm telling you, intensivist to intensivist, if you think you've done everything and you haven't tried this in a timely fashion, you're wrong.
00:56:49
Speaker
And ask the people who've had the exceptional saves using this asset.
00:56:53
Speaker
This is going to help you.
00:56:54
Speaker
It's going to change your clinical practice.
00:56:57
Speaker
And I would like for you to try and tell me if I'm wrong or not.
00:57:00
Speaker
I'm happy to hear the feedback.
00:57:03
Speaker
Excellent.
00:57:04
Speaker
So I think that this is a perfect place to stop Mink.
00:57:07
Speaker
I really appreciate your time and expertise and look forward to talking with you a little bit more.
00:57:12
Speaker
And as data emerges, I mean, hopefully we'll have you back and get more updates.
00:57:17
Speaker
And we will definitely, I mean, stay in touch.
00:57:21
Speaker
Great, Sergio.
00:57:22
Speaker
Thanks very much for the opportunity to talk to your listeners.
00:57:24
Speaker
And I hope you guys have a great Fourth of July weekend.
00:57:26
Speaker
Thank you.
00:57:29
Speaker
Thanks again for listening to critical matters.
00:57:31
Speaker
Make sure to subscribe to this podcast on iTunes or Google play.
00:57:36
Speaker
You can also listen at www.soundphysicians.com backslash podcast.