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Vasopressor Update
11 Plays6 years ago
In our first episode, we discuss the potential role of Angiotensin II for treating shock and review the results of the ATHOS-3 clinical trial.
Our guest is Stephen W. Trzeciak, MD, MPH. Dr. Trzeciak is Interim Chair of Internal Medicine and Head of Critical Care Medicine at Cooper University Health Care. Dr. Trzeciak holds academic appointments as Professor of Medicine and Professor of Emergency Medicine at Cooper Medical School of Rowan University. He is also a prolific investigator and author, with recognized expertise in the treatment of shock, early interventions in critical illness, and the interface between the emergency department and the intensive care unit.
Additional Resources:
- Sound Critical Care webinar on vasopressors. Please review for a more comprehensive discussion on current evidence-based vasopressor use in clinical practice.
- ATHOS-3 clinical trial. Randomized controlled trial evaluating the efficacy of Angiotensin II in raising blood pressure in vasodilatory shock.
- FDA press release. After recording this podcast, the FDA announced the approval of Angiotensin II.
Recommended
Transcript
Introduction and Guest Introduction
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
Today on Critical Matters, we will be discussing new vasopressors.
00:00:28
Speaker
And I'm very excited to introduce our guest, Dr. Steven Triziak,
00:00:33
Speaker
who is the head of critical care medicine, interim chair department of medicine, a professor of medicine and emergency medicine at Cooper Medical School at Rowan University and Cooper University Medical Center in Camden, New Jersey.
00:00:45
Speaker
Dr. Triziak is certified in internal medicine, emergency medicine and critical care medicine.
00:00:50
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He's a prolific author and clinical researcher.
00:00:53
Speaker
Dr. Trzyak is a founding member of the Emergency Medicine Shock Research Network, MShockNet, and his research interests have included early interventions for critical illness and the interface between the emergency department and the ICU with a heavy emphasis on septic shock and cardiac arrest.
00:01:10
Speaker
More recently, Dr. Trzyak's research has focused on the impact of compassion on patient outcomes, healthcare economics, and physician well-being.
00:01:20
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And last but not least, he is a dear, dear friend.
00:01:23
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Welcome, Steve, to Critical Matters.
00:01:27
Speaker
Sergio, thank you so much for having me.
00:01:29
Speaker
I know that sound critical care is a powerhouse in our discipline, and it is indeed an honor to be on the podcast today.
00:01:38
Speaker
Thank you.
00:01:39
Speaker
Excellent.
Vasopressors and ATHES-3 Study Discussion
00:01:40
Speaker
Well, today we're going to talk about vasopressors, specifically angiotensin II.
00:01:45
Speaker
As many of you are aware, in August of 2017, the results of the Angiotensin II for the Treatment of High Output Shock, or ATHES-3, was published in the New England Journal of Medicine.
00:01:56
Speaker
Steve, you had the opportunity to co-author the editorial that was associated with that study in the same issue.
00:02:04
Speaker
So I guess we can start by maybe you could tell us a little bit about Angiotensin II.
00:02:10
Speaker
Sure.
00:02:11
Speaker
Thank you, Sergio.
00:02:12
Speaker
So we've all been in a clinical scenario where we walk into the ICU in the morning and there's a patient in circulatory shock and you find the patient is not just on one vasopressor agent but on multiple.
00:02:30
Speaker
And that can be a harrowing scenario for any intensivist.
00:02:37
Speaker
Unfortunately, it's a very common problem.
00:02:41
Speaker
This paper from the New England Journal of Medicine addresses circulatory shock, patients specifically with vasodilatory shock, and the use of a new agent, angiotensin II, applied above and beyond conventional vasopressor therapy.
00:03:02
Speaker
So our conventional vasopressors that we have for patients with vasodilatory shock, which are
00:03:09
Speaker
as our community is familiar, most commonly is due to sepsis.
00:03:14
Speaker
Those drugs are adrenergic agents like norepinephrine, which is a recommended first-line therapy, and epinephrine, which both have some inotropic and vasopressor effects.
00:03:27
Speaker
Another commonly used agent is vasopressin in low doses that act through the VA1 receptor.
00:03:35
Speaker
And in this study published in the New England Journal of Medicine in August of 2017 is angiotensin II, which works by a different mechanism, a GQ protein stimulation in vascular smooth muscle.
00:03:51
Speaker
And so the hypothesis with testing this agent is that it would raise arterial pressure in patients who already were vasopressor dependent.
Historical Context and ATHOS-3 Trial Insights
00:04:04
Speaker
Excellent.
00:04:04
Speaker
I think that as we all know, our colleagues, our critical care colleagues are always very excited when we have a new toy or a new therapy.
00:04:13
Speaker
This is a new class of drug.
00:04:15
Speaker
But I guess let's dive in a little bit deeper into the actual trial.
00:04:19
Speaker
Could you tell us, Steve, in a little bit more detail, what did the investigators do and report during the ATHES-3 trial?
00:04:29
Speaker
Sure.
00:04:30
Speaker
Now, before I get into the specifics of the trial, you mentioned that we always welcome something new in our practice because it's exciting.
00:04:38
Speaker
You reminded me that actually this isn't entirely new.
00:04:44
Speaker
As a formulation for patients with circulatory shock, it may be new, but the first reports of angiotensin II administration in hemodynamically unstable patients go back actually to
00:04:57
Speaker
50 years.
00:04:58
Speaker
So the notion of treating shock with this agent has actually been around for quite some time.
00:05:08
Speaker
And in fact, in a publication as recently as 2013 in the New England Journal of Medicine, some experts
00:05:20
Speaker
referred to this approach as a as Abandoned meaning we abandoned it as a as an etiology or sorry as a as a therapy for patients with shock But then a very well-designed in my opinion small but well-designed pilot study was done shortly thereafter which showed that
00:05:44
Speaker
angiotensin II administration could reduce norepinephrine requirements in patients with vasothylatory shock.
00:05:50
Speaker
And it was really that pilot study that launched the interest in using it for a therapy and led to the ATHOS trial.
00:05:57
Speaker
And I think those are excellent points, and I agree.
00:06:01
Speaker
I think that
00:06:02
Speaker
As you mentioned, this is one of those cases of a resurrected compound that has a heavy basis on what we know from physiology.
00:06:11
Speaker
So sorry for the interruption, but go ahead and tell us a little more about the ATHOS-3 trial.
00:06:16
Speaker
Sure.
00:06:16
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So the investigators randomly
Safety and Efficacy of Angiotensin II
00:06:21
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assigned patients who were already on norepinephrine, patients with vasodilatory shock, 80% of which were
00:06:30
Speaker
had sepsis as the etiology of shock.
00:06:34
Speaker
They randomized them to angiotensin II or placebo.
00:06:43
Speaker
The end point of the study was a response in blood pressure, meaning a rise in the arterial pressure without any rise in the baseline dose of background vasopressors.
00:06:58
Speaker
And it was a parallel group, two-armed study comparing angiotensin to placebo.
00:07:08
Speaker
What did it show?
00:07:10
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So they randomized 344 patients.
00:07:14
Speaker
And what they found was that the primary endpoint of rise in blood pressure was achieved in the angiotensin group in approximately 70% of the population in the placebo group.
00:07:27
Speaker
less than a quarter of patients.
00:07:29
Speaker
This was highly statistically significant and therefore the primary outcome measure was met.
00:07:38
Speaker
The hypothesis was confirmed that it would in fact raise blood pressure.
00:07:44
Speaker
They did not find any differences in other secondary endpoints, meaning there was no change in the sequential organ failure assessment or SOFIS score.
00:07:57
Speaker
But importantly, they also didn't see any difference in the two groups in the serious adverse events that were reported.
00:08:04
Speaker
As you can imagine, adverse events are common in patients that are this sick.
00:08:08
Speaker
About two-thirds of the population was experiencing adverse events, but there was no significant difference in the adverse event rate between the two groups, angiotensin II and placebo.
00:08:20
Speaker
And I presume that this study was not powered or designed to address a specific benefit in terms of mortality.
00:08:29
Speaker
So it was not.
00:08:30
Speaker
So the primary outcome measure was, in fact, blood pressure.
00:08:35
Speaker
Death, obviously, is something that's reported in all critical care trials.
00:08:38
Speaker
So mortality was compared between the angiotensin 2 groups, the angiotensin 2 group and the placebo group.
00:08:50
Speaker
there was a higher mortality in those patients that were in the placebo arm, but the study was not powered to detect that sort of difference.
00:09:04
Speaker
And so the null hypothesis cannot be rejected.
00:09:07
Speaker
Okay.
00:09:11
Speaker
So I think that with that out, it might be interesting for us to try to really put these results in context and address some questions worth considering to interpret the results and inform our clinical practice.
00:09:28
Speaker
So I guess we could start by asking,
Impact and Alternatives of Angiotensin II
00:09:30
Speaker
did this trial address the safety, the efficacy of angiotensin II in raising blood pressure?
00:09:36
Speaker
So does angiotensin II raise blood pressure?
00:09:41
Speaker
I think the answer to that is pretty clearly yes.
00:09:45
Speaker
That was the primary outcome measure.
00:09:48
Speaker
In my opinion, I'm not entirely surprised.
00:09:51
Speaker
It is known to be a potent vasopressor or vasoconstricting agent, and so while I wasn't surprised by that outcome,
00:10:03
Speaker
I think that it certainly confirmed the hypothesis of the study, and the answer is yes, it raises blood pressure in patients with vasodilatory shock who are already, and this is an important point, who are already requiring support with conventional vasoactive drugs to maintain the blood pressure.
00:10:22
Speaker
And I presume that most of those patients probably were receiving norepinephrine or some similar catecholamine.
00:10:29
Speaker
Most of the patients were on norepinephrine, that's correct.
00:10:32
Speaker
And I think for our audience, as you mentioned, Stephen, a very important distinction is that these were patients who were already receiving fluids and were on a vasopressor agent.
00:10:43
Speaker
So did it talk about, did it address the safety?
00:10:45
Speaker
Do you think agent tension 2 is safe based on what we've seen from this trial?
00:10:51
Speaker
Based on what we see in this particular study, it appears to be safe in that there was not a
00:11:01
Speaker
difference in serious adverse events between the groups.
00:11:06
Speaker
In fact, numerically, it was slightly lower in the angiotensin II group.
00:11:13
Speaker
But there was โ the study wasn't powered to that endpoint of serious adverse events.
00:11:22
Speaker
Obviously, it was powered to an efficacy standpoint or from an efficacy endpoint.
00:11:31
Speaker
So there is no signal in these data that would let us conclude that it wasn't safe.
00:11:40
Speaker
We always have some caution in that in subsequent evaluations or in clinical practice, other findings sometimes come up, but there's certainly nothing in this study that would be an important safety signal or anything that would
00:12:00
Speaker
be a red flag, so to speak.
00:12:02
Speaker
It appears to be safe.
00:12:04
Speaker
The only caveat would be that this is just one study of 344 patients.
00:12:09
Speaker
Correct.
00:12:10
Speaker
Now, Steve, could you comment on were there any specific complications or specific patient groups that might be more prone to complications with the use of angiotensin II?
00:12:25
Speaker
Well, the short answer to your question is we don't know.
00:12:29
Speaker
One potential group that we would have be especially cautious with are those patients who have low cardiac output despite having vasodilatory shock.
00:12:45
Speaker
We're aware of the fact that in septic shock, for example, a
00:12:51
Speaker
small but distinct population of patients may have profound myocardial depression as part of their shock profile and sepsis.
00:12:59
Speaker
And in other studies, for example, in the randomized control trial years ago of a non-selected nitric oxide synthase inhibitor, they found that there was a signal of harm in a subgroup of patients
00:13:21
Speaker
that had a low cardiac index, and so they seem to be particularly intolerant of high doses of the drug.
00:13:31
Speaker
We have no information on that specifically with regards to angiotensin.
00:13:39
Speaker
I just would point out that that is probably a special population in which all intensivists should proceed with caution.
00:13:50
Speaker
because we don't know what potent vasoconstriction might do to their cardiac output.
00:13:56
Speaker
And I know that you are a big believer of the potential periods of consequences down the road that we did not foresee, and that might be one of them that we could have with a drug like this.
00:14:10
Speaker
So I definitely believe that these are questions that we should have in mind as we treat patients, but also excellent questions for future clinical trials.
00:14:21
Speaker
Yeah, one thing I would probably like to mention is that there's no signal in the data in this study that would make us think that that small subset of the population might have adverse effects with the drug.
00:14:39
Speaker
I'd just raise it as an example of a population that might need special considerations.
00:14:46
Speaker
And that's true for any drug in its development.
00:14:50
Speaker
that there may be special populations that require additional considerations.
00:14:57
Speaker
Steve, do you think that angiotensin II could be an alternative to or a replacement of other vasopressors that are currently in use, and was that addressed in this study?
00:15:09
Speaker
Yeah, I don't know the answer to your question because we have to keep in mind that all the patients in this study were already on vasopressor agents.
00:15:20
Speaker
They were either requiring a moderate dose of norepinephrine or some equivalent dose of another vasopressor.
00:15:28
Speaker
So there was no, I should say in this study, it wasn't tested as a first-line agent, like a go-to drug.
00:15:42
Speaker
Perhaps it could be a go-to drug, but those studies have not yet been conducted.
00:15:46
Speaker
And the current randomized control trial, very well designed, by the way, a really nice study.
00:15:55
Speaker
But the current study doesn't give us any information on whether or not it could be a first-line drug.
00:16:01
Speaker
It just wasn't designed to do that.
00:16:05
Speaker
Do we have any evidence that antitensin 2 improves patient outcomes?
00:16:09
Speaker
Does it actually make our patients better?
00:16:14
Speaker
Yeah, that's a great question.
00:16:16
Speaker
And I guess a more fundamental question would be, does it have to?
00:16:23
Speaker
What I mean by that is, although in patients with circulatory shock and clinical trials of shock patients, and specifically, let's say, septic shock patients, because the majority of patients in this study had shock due to sepsis,
00:16:41
Speaker
we typically talk about 28-day mortality as the primary endpoint.
00:16:45
Speaker
This wasn't.
00:16:45
Speaker
This was a study of a vasopressor agent to raise the blood pressure.
00:16:49
Speaker
And while we're used to thinking about what's the impact on mortality or what's the impact on organ failure as a surrogate outcome that's clinically meaningful,
00:17:08
Speaker
I think it's important to keep in mind that the current agents that we use, like norepinephrine, for example, there's no data there that norepinephrine improves mortality over other agents.
00:17:22
Speaker
And so just raising the blood pressure, because in your practice, Sergio, and in mine, we likely use norepinephrine perhaps every day, and there's no evidence that that improves mortality.
00:17:37
Speaker
It's just intuitive that if somebody's got profoundly low blood pressure, you have to fix it.
00:17:42
Speaker
And norepinephrine, for example, is really a potent vasopressor that raises the blood pressure.
00:17:47
Speaker
And there's a certain intuitiveness that that's a good thing or it's a necessary thing in order to give the patient a chance to survive the illness.
00:17:59
Speaker
We know that profoundly low blood pressure is associated with harm.
00:18:03
Speaker
That's not surprising to anyone.
00:18:05
Speaker
And so I guess a fundamental first question before I answer your question of does it make people better is what are we really asking our drugs to do or what are we asking in this case our vasopressors to do?
00:18:18
Speaker
I wouldn't expect a trial of norepinephrine and similarly designed trial of norepinephrine to have a mortality benefit.
00:18:26
Speaker
So why would I think that angiotensin 2 should have a mortality benefit?
00:18:31
Speaker
Does that make sense?
00:18:32
Speaker
It does, and I think you raise an excellent point that sometimes maybe we are expecting too much from certain therapies that are emerging.
00:18:40
Speaker
And I think you very nicely put in context what we know of what we usually are using or what we actually are using these days and how that would compare to a potential new drug.
00:18:51
Speaker
And I think it's a great point, Steve.
00:18:54
Speaker
Well, the clinically relevant question then would be as a go-to drug, is it better at achieving arterial pressure targets than the drugs you're used to using
Future Research and Clinical Significance
00:19:03
Speaker
every day?
00:19:03
Speaker
And like we said earlier, that just wasn't tested in this study.
00:19:09
Speaker
It might, but we just don't have that information yet.
00:19:12
Speaker
And I think that also from the physiological standpoint, that's always been a very important
00:19:18
Speaker
potentially dangerous route to take when we go to clinical trials.
00:19:22
Speaker
But it makes sense that if we could utilize agents that act on different pathways, we could probably provide more balance and some benefit to our patients.
00:19:31
Speaker
So I think these are all great questions that we don't have answers to, but that hopefully down the road future studies could address and try to answer.
00:19:39
Speaker
Now you asked me if it makes patients better in general.
00:19:44
Speaker
One of the things that I think is important from this study, just hypothesis generating perhaps, is that if a drug was going to help a patient survive the illness in circulatory shock, typically we would think that it would
00:20:11
Speaker
impact the progression or development of multiple organ dysfunction given the fact that the mode of death in patients with circulatory shock who don't have a sudden cardiac arrest is typically progressive multiple organ dysfunction.
00:20:26
Speaker
So we did not, the investigators did not find a difference in the sequential organ failure assessment score.
00:20:39
Speaker
So we did not see a physiological signal that multi-organ failure was being modulated in some way.
00:20:47
Speaker
And I think that that is important data because of the fact that there was a
00:21:01
Speaker
a numerical, although not statistically significant difference in death in favor of angiotensin II, which was not statistically significant, so the null hypothesis cannot be rejected.
00:21:12
Speaker
But the fact that the SOFA score was flat would make me think that there may not be a survival benefit, despite the fact that there might be an interesting signal in the mortality difference
00:21:30
Speaker
published in this study.
00:21:32
Speaker
But like I said, I wouldn't expect a potent vasopressor, which angiotensin is.
00:21:39
Speaker
It's a quite potent vasopressor.
00:21:41
Speaker
I wouldn't necessarily have that expectation.
00:21:45
Speaker
So I don't think that's what we're asking our vasopressors to do necessarily.
00:21:52
Speaker
And I think that going back to your previous point,
00:21:54
Speaker
In this particular trial, the placebo plus norepinephrine group did not have a difference in the SOFA scores either.
00:22:02
Speaker
Is that correct?
00:22:04
Speaker
That's right.
00:22:06
Speaker
So is angiotensin II available for clinical use by clinicians right now?
00:22:13
Speaker
Not at the present time, to the best of my knowledge.
00:22:17
Speaker
And I don't know what sort of process is in the works for making it a consideration at the bedside.
00:22:24
Speaker
I'm not privy to that sort of information, but it's certainly something that, in my opinion, is promising.
00:22:31
Speaker
We just have to see how everything evolves.
00:22:34
Speaker
And I think as you summed it up very nicely in your editorial, there's a lot of promise, but there's also caution, which we've addressed.
Personal Insights from Dr. Triziak
00:22:42
Speaker
I think that we will stay tuned into future studies, but also into the process for this drug potentially coming to market.
00:22:52
Speaker
And I'm sure that we'll have some comments from you back then when that occurs.
00:22:58
Speaker
Steve, I would like to close with some questions that we like to
00:23:04
Speaker
pose to our guests in critical matters just to tap into their wisdom and talk about other aspects that we think are as relevant as the clinical aspects to the practice of critical care medicine.
00:23:16
Speaker
Would that be okay?
00:23:17
Speaker
Sure.
00:23:17
Speaker
Yeah, sure.
00:23:19
Speaker
So I would like to know if there is a specific book or books that have influenced you significantly, or is there a book that you have gifted most often to others?
00:23:30
Speaker
So without a doubt, from a personal standpoint, that book would be the Bible.
00:23:35
Speaker
But from a professional standpoint, I like the book Start With Why.
00:23:40
Speaker
That is a book by the author Simon Sinek.
00:23:42
Speaker
And the reason why I like it is if you don't know why you're doing something, you're not going to ever figure out what you're doing.
00:23:49
Speaker
And I think in terms of gifting.
00:23:52
Speaker
Sorry, go ahead.
00:23:52
Speaker
Go ahead.
00:23:54
Speaker
In terms of gifting to others, I really like a book by the author's name is Sean Acor.
00:24:00
Speaker
It's called The Happiness Advantage.
00:24:02
Speaker
And it essentially gives you all the data in the scientific literature that if you find your happiness, you'll likely be more successful rather than the conventional thinking, which is the other way around.
00:24:21
Speaker
And I think, Steve, that these are two excellent examples of books that a
00:24:26
Speaker
I think have tremendous wisdom to the practice of critical care and to intensivist.
00:24:32
Speaker
I think that the Simon Sinek book that you mentioned, Start With A Why, very nicely presents a framework to organize your thoughts in terms of why are you doing what you're doing, how are you doing differently than others, and ultimately what are you doing, which in this case for us is practicing critical care, but the other two I think are much more profound and important questions to answer.
00:24:55
Speaker
And to the Sean Acker book, I think that, as you mentioned, the happiness advantage, it really flips the paradigm that we've had.
00:25:04
Speaker
If I work hard enough, eventually I will be happy, to if I'm happy, I will be very productive and very efficient at work.
00:25:11
Speaker
And I think in a time where burnout is so prevalent in the medical field, that is definitely, I think, a read worth taking for our intensivist.
00:25:22
Speaker
I couldn't agree more.
00:25:24
Speaker
Is there something that you believe to be true in medicine or in life that most other people don't believe?
00:25:33
Speaker
Oh, that's probably true on a lot of things, but it doesn't mean that I'm right about it.
00:25:37
Speaker
One thing I am especially convicted about that I am in the process of developing a scientific program to test hypotheses in this area.
00:25:48
Speaker
I think that historically in medicine, we've
00:25:55
Speaker
had this paradigm where the science of medicine and the art of medicine are completely apart from each other.
00:26:06
Speaker
There's a divide between the science of medicine and the art of medicine.
00:26:10
Speaker
And what I mean by that in the art of medicine is not just treating people, but taking care of them, connecting with them, showing them compassion.
00:26:19
Speaker
I think that there is compelling scientific data
00:26:24
Speaker
that compassion for patients is not only meaningful in terms of improving health outcomes, but also in making healthcare better and also making the healthcare provider experience better.
00:26:40
Speaker
So I don't necessarily believe that
00:26:44
Speaker
the science of medicine and the art of medicine are as distinct as we're historically taught.
Closing Advice and Podcast Conclusion
00:26:50
Speaker
Rather, I think that there's actually science in the art and that science is strong.
00:26:57
Speaker
Finally, is there anything that you would want every sound critical care intensivist to know?
00:27:06
Speaker
A mentor of mine just when I started training used to tell me one thing every time we would step into the patient care arena.
00:27:16
Speaker
He just looked me square in the eyes and he said, be careful.
00:27:19
Speaker
I can't tell you how many times that that has rung true for me in my life.
00:27:24
Speaker
And so I try to remind myself of that every day.
00:27:29
Speaker
You know, we all carry into our clinical practice
00:27:33
Speaker
whatever mental or emotional baggage we may have.
00:27:38
Speaker
We may be having the worst day of the year, but when you walk onto the unit, when you're on the deck, you're on.
00:27:48
Speaker
Those patients are depending on you.
00:27:51
Speaker
I think be careful is something that I just remind myself of, not every day, but literally every hour when I'm making rounds.
00:28:00
Speaker
And I think that is excellent advice, Steve.
00:28:02
Speaker
I think that it applies very deeply to what we do as intensivists.
00:28:07
Speaker
And I think it also relates to what you were talking about earlier about merging the science and the art and thinking about compassion and how it really impacts our patients.
00:28:19
Speaker
I want to really thank you for your time, for sharing with us your thoughts.
00:28:23
Speaker
We will definitely have you back on the podcast soon to discuss other aspects of critical care and other areas that I think are of great interest for our audience, but also that I know that you're very passionate and knowledgeable.
00:28:38
Speaker
So, Steve, I hope you have a great rest of the year.
00:28:41
Speaker
Thank you very much for your time.
00:28:45
Speaker
Thank you so much, Sergio.
00:28:46
Speaker
Take care.
00:28:49
Speaker
Thanks again for listening to Critical Matters.
00:28:52
Speaker
Make sure to subscribe to this podcast on iTunes or Google Play.