Transcript
Speaker: Welcome to Critical Matters, a sound critical care podcast covering a broad range of topics related to the practice of intensive care medicine.
Speaker: And now, your host, Dr. Sergio Zanotti.
Speaker: Today on Critical Matters, we will be discussing new vasopressors.
Speaker: And I'm very excited to introduce our guest, Dr. Steven Triziak,
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.
Speaker: Dr. Triziak is certified in internal medicine, emergency medicine and critical care medicine.
Speaker: He's a prolific author and clinical researcher.
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.
Speaker: More recently, Dr. Trzyak's research has focused on the impact of compassion on patient outcomes, healthcare economics, and physician well-being.
Speaker: And last but not least, he is a dear, dear friend.
Speaker: Welcome, Steve, to Critical Matters.
Speaker: Sergio, thank you so much for having me.
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.
Speaker: Thank you.
Speaker: Excellent.
Speaker: Well, today we're going to talk about vasopressors, specifically angiotensin II.
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.
Speaker: Steve, you had the opportunity to co-author the editorial that was associated with that study in the same issue.
Speaker: So I guess we can start by maybe you could tell us a little bit about Angiotensin II.
Speaker: Sure.
Speaker: Thank you, Sergio.
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.
Speaker: And that can be a harrowing scenario for any intensivist.
Speaker: Unfortunately, it's a very common problem.
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.
Speaker: So our conventional vasopressors that we have for patients with vasodilatory shock, which are
Speaker: as our community is familiar, most commonly is due to sepsis.
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.
Speaker: Another commonly used agent is vasopressin in low doses that act through the VA1 receptor.
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.
Speaker: And so the hypothesis with testing this agent is that it would raise arterial pressure in patients who already were vasopressor dependent.
Speaker: Excellent.
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.
Speaker: This is a new class of drug.
Speaker: But I guess let's dive in a little bit deeper into the actual trial.
Speaker: Could you tell us, Steve, in a little bit more detail, what did the investigators do and report during the ATHES-3 trial?
Speaker: Sure.
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.
Speaker: You reminded me that actually this isn't entirely new.
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
Speaker: 50 years.
Speaker: So the notion of treating shock with this agent has actually been around for quite some time.
Speaker: And in fact, in a publication as recently as 2013 in the New England Journal of Medicine, some experts
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
Speaker: angiotensin II administration could reduce norepinephrine requirements in patients with vasothylatory shock.
Speaker: And it was really that pilot study that launched the interest in using it for a therapy and led to the ATHOS trial.
Speaker: And I think those are excellent points, and I agree.
Speaker: I think that
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.
Speaker: So sorry for the interruption, but go ahead and tell us a little more about the ATHOS-3 trial.
Speaker: Sure.
Speaker: So the investigators randomly assigned patients who were already on norepinephrine, patients with vasodilatory shock, 80% of which were
Speaker: had sepsis as the etiology of shock.
Speaker: They randomized them to angiotensin II or placebo.
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.
Speaker: And it was a parallel group, two-armed study comparing angiotensin to placebo.
Speaker: What did it show?
Speaker: So they randomized 344 patients.
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.
Speaker: less than a quarter of patients.
Speaker: This was highly statistically significant and therefore the primary outcome measure was met.
Speaker: The hypothesis was confirmed that it would in fact raise blood pressure.
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.
Speaker: But importantly, they also didn't see any difference in the two groups in the serious adverse events that were reported.
Speaker: As you can imagine, adverse events are common in patients that are this sick.
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.
Speaker: And I presume that this study was not powered or designed to address a specific benefit in terms of mortality.
Speaker: So it was not.
Speaker: So the primary outcome measure was, in fact, blood pressure.
Speaker: Death, obviously, is something that's reported in all critical care trials.
Speaker: So mortality was compared between the angiotensin 2 groups, the angiotensin 2 group and the placebo group.
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.
Speaker: And so the null hypothesis cannot be rejected.
Speaker: Okay.
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.
Speaker: So I guess we could start by asking, did this trial address the safety, the efficacy of angiotensin II in raising blood pressure?
Speaker: So does angiotensin II raise blood pressure?
Speaker: I think the answer to that is pretty clearly yes.
Speaker: That was the primary outcome measure.
Speaker: In my opinion, I'm not entirely surprised.
Speaker: It is known to be a potent vasopressor or vasoconstricting agent, and so while I wasn't surprised by that outcome,
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.
Speaker: And I presume that most of those patients probably were receiving norepinephrine or some similar catecholamine.
Speaker: Most of the patients were on norepinephrine, that's correct.
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.
Speaker: So did it talk about, did it address the safety?
Speaker: Do you think agent tension 2 is safe based on what we've seen from this trial?
Speaker: Based on what we see in this particular study, it appears to be safe in that there was not a
Speaker: difference in serious adverse events between the groups.
Speaker: In fact, numerically, it was slightly lower in the angiotensin II group.
Speaker: But there was – the study wasn't powered to that endpoint of serious adverse events.
Speaker: Obviously, it was powered to an efficacy standpoint or from an efficacy endpoint.
Speaker: So there is no signal in these data that would let us conclude that it wasn't safe.
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
Speaker: be a red flag, so to speak.
Speaker: It appears to be safe.
Speaker: The only caveat would be that this is just one study of 344 patients.
Speaker: Correct.
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?
Speaker: Well, the short answer to your question is we don't know.
Speaker: One potential group that we would have be especially cautious with are those patients who have low cardiac output despite having vasodilatory shock.
Speaker: We're aware of the fact that in septic shock, for example, a
Speaker: small but distinct population of patients may have profound myocardial depression as part of their shock profile and sepsis.
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
Speaker: that had a low cardiac index, and so they seem to be particularly intolerant of high doses of the drug.
Speaker: We have no information on that specifically with regards to angiotensin.
Speaker: I just would point out that that is probably a special population in which all intensivists should proceed with caution.
Speaker: because we don't know what potent vasoconstriction might do to their cardiac output.
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.
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.
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.
Speaker: I'd just raise it as an example of a population that might need special considerations.
Speaker: And that's true for any drug in its development.
Speaker: that there may be special populations that require additional considerations.
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?
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.
Speaker: They were either requiring a moderate dose of norepinephrine or some equivalent dose of another vasopressor.
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.
Speaker: Perhaps it could be a go-to drug, but those studies have not yet been conducted.
Speaker: And the current randomized control trial, very well designed, by the way, a really nice study.
Speaker: But the current study doesn't give us any information on whether or not it could be a first-line drug.
Speaker: It just wasn't designed to do that.
Speaker: Do we have any evidence that antitensin 2 improves patient outcomes?
Speaker: Does it actually make our patients better?
Speaker: Yeah, that's a great question.
Speaker: And I guess a more fundamental question would be, does it have to?
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,
Speaker: we typically talk about 28-day mortality as the primary endpoint.
Speaker: This wasn't.
Speaker: This was a study of a vasopressor agent to raise the blood pressure.
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,
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.
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.
Speaker: It's just intuitive that if somebody's got profoundly low blood pressure, you have to fix it.
Speaker: And norepinephrine, for example, is really a potent vasopressor that raises the blood pressure.
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.
Speaker: We know that profoundly low blood pressure is associated with harm.
Speaker: That's not surprising to anyone.
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?
Speaker: I wouldn't expect a trial of norepinephrine and similarly designed trial of norepinephrine to have a mortality benefit.
Speaker: So why would I think that angiotensin 2 should have a mortality benefit?
Speaker: Does that make sense?
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.
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.
Speaker: And I think it's a great point, Steve.
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 every day?
Speaker: And like we said earlier, that just wasn't tested in this study.
Speaker: It might, but we just don't have that information yet.
Speaker: And I think that also from the physiological standpoint, that's always been a very important
Speaker: potentially dangerous route to take when we go to clinical trials.
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.
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.
Speaker: Now you asked me if it makes patients better in general.
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
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.
Speaker: So we did not, the investigators did not find a difference in the sequential organ failure assessment score.
Speaker: So we did not see a physiological signal that multi-organ failure was being modulated in some way.
Speaker: And I think that that is important data because of the fact that there was a
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.
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
Speaker: published in this study.
Speaker: But like I said, I wouldn't expect a potent vasopressor, which angiotensin is.
Speaker: It's a quite potent vasopressor.
Speaker: I wouldn't necessarily have that expectation.
Speaker: So I don't think that's what we're asking our vasopressors to do necessarily.
Speaker: And I think that going back to your previous point,
Speaker: In this particular trial, the placebo plus norepinephrine group did not have a difference in the SOFA scores either.
Speaker: Is that correct?
Speaker: That's right.
Speaker: So is angiotensin II available for clinical use by clinicians right now?
Speaker: Not at the present time, to the best of my knowledge.
Speaker: And I don't know what sort of process is in the works for making it a consideration at the bedside.
Speaker: I'm not privy to that sort of information, but it's certainly something that, in my opinion, is promising.
Speaker: We just have to see how everything evolves.
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.
Speaker: I think that we will stay tuned into future studies, but also into the process for this drug potentially coming to market.
Speaker: And I'm sure that we'll have some comments from you back then when that occurs.
Speaker: Steve, I would like to close with some questions that we like to
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.
Speaker: Would that be okay?
Speaker: Sure.
Speaker: Yeah, sure.
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?
Speaker: So without a doubt, from a personal standpoint, that book would be the Bible.
Speaker: But from a professional standpoint, I like the book Start With Why.
Speaker: That is a book by the author Simon Sinek.
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.
Speaker: And I think in terms of gifting.
Speaker: Sorry, go ahead.
Speaker: Go ahead.
Speaker: In terms of gifting to others, I really like a book by the author's name is Sean Acor.
Speaker: It's called The Happiness Advantage.
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.
Speaker: And I think, Steve, that these are two excellent examples of books that a
Speaker: I think have tremendous wisdom to the practice of critical care and to intensivist.
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.
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.
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.
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.
Speaker: I couldn't agree more.
Speaker: Is there something that you believe to be true in medicine or in life that most other people don't believe?
Speaker: Oh, that's probably true on a lot of things, but it doesn't mean that I'm right about it.
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.
Speaker: I think that historically in medicine, we've
Speaker: had this paradigm where the science of medicine and the art of medicine are completely apart from each other.
Speaker: There's a divide between the science of medicine and the art of medicine.
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.
Speaker: I think that there is compelling scientific data
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.
Speaker: So I don't necessarily believe that
Speaker: the science of medicine and the art of medicine are as distinct as we're historically taught.
Speaker: Rather, I think that there's actually science in the art and that science is strong.
Speaker: Finally, is there anything that you would want every sound critical care intensivist to know?
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.
Speaker: He just looked me square in the eyes and he said, be careful.
Speaker: I can't tell you how many times that that has rung true for me in my life.
Speaker: And so I try to remind myself of that every day.
Speaker: You know, we all carry into our clinical practice
Speaker: whatever mental or emotional baggage we may have.
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.
Speaker: Those patients are depending on you.
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.
Speaker: And I think that is excellent advice, Steve.
Speaker: I think that it applies very deeply to what we do as intensivists.
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.
Speaker: I want to really thank you for your time, for sharing with us your thoughts.
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.
Speaker: So, Steve, I hope you have a great rest of the year.
Speaker: Thank you very much for your time.
Speaker: Thank you so much, Sergio.
Speaker: Take care.
Speaker: Thanks again for listening to Critical Matters.
Speaker: Make sure to subscribe to this podcast on iTunes or Google Play.
