The CAPITAL DOREMI 2 study is a multi-centre, double-blind, randomized controlled trial which assessed the safety and efficacy of inotrope therapy versus placebo in treating patients with SCAI class C to D cardiogenic shock.
In this video interview, Drs. Nick Smith (Johns Hopkins Hospital) and Pooja Prasad (OHSU) of the CardioNerds spoke with CAPITAL DOREMI 2 researchers Drs. Rebecca Mathew (University of Ottawa, Principal Investigator), and Benjamin Hibbert (University of Ottawa) about this study, and its significance.
Dr. Nick Smith: Hello everyone. My name’s Nick Smith. I’m currently fourth year cardiology and critical care medicine fellow and chief fellow at the Johns Hopkins Hospital. I’m excited to be here today to discuss the inotrope versus placebo therapy for cardiogenic shock CAPITAL DOREMI 2 trial and so I’m happy everybody can be here.
Dr. Pooja Prasad: Hi everyone. My name is Pooja and I’m a third-year cardiology fellow and Cardio Nerds ambassador at OHSU currently applying for advanced heart failure. I’m so excited to be part of this multidisciplinary discussion. Dr. Benjamin Hibbert is an interventional cardiologist and assistant professor in the department of Medicine at the University of Ottawa.
Dr. Nick Smith: And Dr. Rebecca Matthew is a cardiologist in critical care medicine specialist at the University of Ottawa as well where she’s also an assistant professor in the faculty of medicine. So, we’ll start I guess, with you Dr. Matthew. So as a bit of background, the milrinone compared to dobutamine in treatment of cardiogenic shock trial, the original DOREMI trial in 2021. It was a big topic of discussion, at least in our fellowship as the comparison of these two agents had really long been debated. There’s the classic discussion that really set out to try to answer a question of, what might be superior or are they more or less equivalent? So, this study compared milrinone to dobutamine and concluded there was no significant difference in a composite outcome. But this trial attempts to ask a more basic question, are either of these agents superior to placebo?
Dr. Nick Smith: And I think the dogma here is that inotropes of course are helpful in cardiogenic shock. Anecdote would tell us this, but we have no randomized control trial data to support it. And at least if you look at IBP shock too, as a reminder, it often happens in cardiology that we think that something is effective and it might have an improvement in mortality, and then it turns out that doesn’t pan out in randomized control trials. So I guess long winded intro, but I’ll turn to you Dr. Matthews and just ask if you could just talk a little bit about your motivations for running this trial and whether you encountered any ethical hurdles since you’re suggesting a placebo arm of normal saline against what is already considered standard of care and just how you guys crafted it.
Dr. Rebecca Mathew: Yeah, thanks so much for the kind introduction and obviously having Ben and I here, it’s really wonderful to have this opportunity. So, I mean, that’s a great summary and introduction. I couldn’t have said it better myself. I think the biggest motivation for running this trial is what Dr. Hibbert actually said to me when I was a first year cardiology resident, which is that anyone who has a vested interest in doing awesome clinical medicine should have that same passion for clinical research because the best clinical questions- Or sorry, the best research questions really arise from what we do at the bedside as clinicians because ultimately all the research that we do, we really want to translate that to taking care of a specific patient at the bedside and have better outcomes. So, with that being said, as you highlighted, dogma drives so many of the decisions that we make, and dogma is really hard to change.
Dr. Rebecca Mathew: And within critical care and cardiology in so many other areas of medicine, we have challenged dogma what we believe to be unshakeable, unquestionable and we’ve proved ourselves wrong over and over again. So, look at PARAMEDIC, look at NICE-SUGAR, you can look at TOTAL, you can look at CAST one and two, we’ve done this over and over again. You talked about IBP shock. And so, for Ben and I, when we initially set out to craft DOREMI, the first one in terms of mil versus dob, we wanted to start addressing that dogma but do it in baby steps. And so, we thought to withhold inotrope completely is pretty stressful for other people. So that’s why we thought mil versus dob. And then once we did that trial, we felt like we had enough runway and lead in order to approach this inotrope versus placebo in the early resuscitation period. And so, I think that’s the second question to be answered.
Dr. Rebecca Mathew: The third question, which I’m more interested in is prolonging that placebo intervention for more than 12 hours. So now you’re talking about days, duration of hospitalization and really starting to answer these questions around what is the harm benefit scale and where does that end up in managing these patients. So hopefully that’s a bit of an answer. I apologize if that’s a bit long winded. And then in terms of the second thing that you asked, the ethical hurdles, oh dear, there were many. Not so much in terms of the actual REB and process of doing ethics. I mean that’s very standardized and algorithmic, and it just demonstrates the importance of doing really detailed literature review before you start undertaking these types of trials. So, this is where I think systematic reviews and meta-analysis are really important. Understanding the literature is really important and going in really informed about what the body of literature is around the specific question that you’re trying to ask.
Dr. Rebecca Mathew: More interesting ethical hurdles are working with a larger group of people where everyone has really years and years of experience and a lot of strongly formed opinions in terms of what they want to do in caring for these patients. And so, it was a lot of buy-in, getting people on board in terms of understanding the protocol and getting comfortable with randomizing these patients. And that was just something that took time. We’re lucky to work in a really supportive center and ultimately DOREMI 2 is going really well as well. So, I’ll stop there. Sorry, that was a bit long.
Dr. Nick Smith: No, it’s a great answer. Thank you.
Dr. Pooja Prasad: No, that was fine. Thank you so much for that background, Dr. Matthew. Obviously those of us reading the trial don’t realize you and Dr. Hibbert had already thought of DOREMI 2 prior to conducting DOREMI 1. So, thank you for that background. I’m going to now direct a question to Dr. Hibbert and obviously when we’re thinking about how we apply our evidence to our patients, it’s so important for us to think, did our patient even meet inclusion criteria for whatever study? And so, Dr. Hibbert, my question is about inclusion and exclusion.
Dr. Pooja Prasad: A recent analysis from the Cardiogenic Shock Working Registry released on July 19th in JACC that arguing that stage B shock as being either hypotension or hypoperfusion. Arguing there’s a significant portion of patients that are normotensive with hypoperfusion in early shock. In the same paper they show data that 90% of stage B patients will progress to stage D or E and state that this is a key cohort to consider. I wonder if you could talk about how you balance inclusion and exclusion with your trials, specifically not including patients who are in stage B and also excluding stage E. And this approach was obviously in contrast to the first CAPITAL DOREMI, a trial comparing milrinone to dobutamine and cardiogenic shock, which included patients with SCAI stage B to E.
Dr. Benjamin Hibbert: Yeah, so great question. I mean ultimately, you can design trials to treat that perfect patient population, or you can design your trials to be as pragmatic as possible to reflect the kind of patients that you treat. And when we set up to do DOREMI 1, so to be clear, the SCAI criteria weren’t even published. So, when we started DOREMI, we had inclusion criteria that reflected inclusion criteria from a number of shock trials but were broadly designed to include the patients that we would want to treat with inotropes. And then as the SCAI criteria were published and while we were running the trial, we adopted those criteria in a retrospective manner of the patient population to classify them. So, in DOREMI 1 which ultimately ended up being a trial SCAI C and D, that was over 95% of the patient population.
Dr. Benjamin Hibbert: I had a couple patients in SCAI E and a couple patients in SCAI B. But really what we were trying to capture or what the spirit of the trial was to treat those patients that we would normally treat with inotropes. So, when we were rounding [inaudible], this would be the type of patient that we came along. And obviously the SCAI classification has completely changed the way that we talk and communicate to each other about shock patients. And I think that’s a good thing because it’s really standardized some of the nomenclature around these patients. However, it’s important to highlight that there’s still a lot of gray in how we classify these patients. So, the paper that you refer to in July 19th I think does a great job because it really puts more firm parameters about what classifies you as a stage B and what classifies you as a stage C.
Dr. Benjamin Hibbert: However, those are still arbitrary cutoffs and while they’re being designed to predict prognosis, I’m not sure everyone that would read those would necessarily agree with those guidelines. And even if you read the paper earlier in the year in JACC on the definitions, one of the things they define is differentiated between SCAI B and SCAI C was the presence of sodium lactate. So that would be in contradiction to a later paper. So, I think even in the field, these definitions are evolving. That being said, when we went to do DOREMI 2, we really wanted to again reflect those patients that we would normally treat with an inotrope in the day to day rounding in a cardiac intensive care unit. And so, we felt that that was best reflected in including SCAI C and SCAI D patients. You’re absolutely right though, SCAI B I think with that paper that came out, earlier interventions in those patients, especially if that large of a cohort is progressing to SCAI D and E, preventing the march of shock, it is probably going to be a therapeutic target.
Dr. Benjamin Hibbert: I mean the reality of all of this is these patients are going through these SCAI classifications at various phases of those shocks. So, the SCAI B shock, or the SCAI E shock patient that you meet was SCAI B at some point. It’s just when you end up meeting them. And so ultimately, this is all one disease and we felt that most people would be agreeable to treating SCAI C and D patients with inotropes. Those are the patients that we would normally treat. And so, we wanted to make the trial as pragmatic as possible. And if you look at the inclusion criteria, you know have to be 18, you have to be SCAI C or D, and you have to want to treat them with an inotrope. We excluded patients without a hospital cardiac arrest. And that is one thing that I find is very conflated in the SCAI definitions.
Dr. Benjamin Hibbert: I don’t think out of hospital cardiac arrest patients should be in that cohort. They usually have a neurologic death. It’s very rare that we don’t resuscitate patients from their cardiogenic shock in the context around a hospital cardiac arrest. So that adds a lot of confounding. You can’t have a dynamic outflow tract obstruction because obviously we don’t want to make that worse and you can’t have been on milrinone or dobutamine. And that’s actually the number one exclusion is that patients are transferred to us already with an inotrope on. And so obviously the hypothesis of the study is that inotropes will facilitate the resuscitation of these patients in early [inaudible]. And so, if they come on and inotrope we can’t enroll them. So, these are broad inclusive inclusion criteria, very limited excluding criteria to try to make this as pragmatic and reflective of the care that you guys provide to your patients every day.
Dr. Nick Smith: No, that’s such a great answer and it’s right, there are such fluid stages that you still will capture all of the patients just a different time. So, I really appreciate the way that you answered that. I will turn to you again Dr. Matthew with just saying, so one of the interesting things that for me as a soon to be minted cardiac intensivist, I guess if anybody hires me, there’s always that, but is the variability in regards to how an attending will track and make adjustments to therapy. So just thinking about the variability, even in my own ICU, forget across ICUs because obviously every institution has their own inborn processes and their own ways that they do things.
Dr. Nick Smith: I know we have intensivists who will do it but will adjust their inotropes tropes by Swan numbers, others to urine output and symptoms and more esoteric, that lactate things as well. So will your study, I guess, require a protocol for titration, and if so, how will you balance the various styles that some physicians would escalate? So, for instance, I could imagine that some physicians might escalate slowly or some too quickly and each would necessarily have its problem in a randomized control trial. So, do you guys aim to address that or what are your thoughts there?
Dr. Rebecca Mathew: Yeah, so I think that’s definitely a really pragmatic, practical question that we had to try to answer. As you highlighted, there’s really no evidence to support titrating therapy to any specific thing like symptoms, hemodynamics. What we do, I think generally what I’ve seen is really focus on markers of end organ perfusion and try to normalize that or what we think is normal and there’s even some variability from center from that perspective. We very recently in the last month or so, published a JACC: Advances paper where we looked at perfusion targets in cardiogenic shock. And I think one of the things we really tried to highlight was that there is not a lot of data to guide this resuscitation. And so ultimately it comes down to what your experience was as a trainee, what the people who trained you did, and what you’ve seen work anecdotally.
Dr. Rebecca Mathew: So, I think with that as the background, we really made a point of not providing a standardized titration protocol and specific points and guidelines to the physicians. What we told people is these are the common doses that are used. So, we have stage one to stage five, so starting at 2.5 of dob or 0.125 of mil, and then titrating up in the usual stages, 0.25, 0.37, 0.5, 2.55, 7.510 because that’s what we’ve sort of seen at least across Ontario and in Canada in terms of standardized doses. But we’ve essentially told the physician, you titrate the drug according to what you feel you would normally do. We wanted to make this pragmatic, we wanted to replicate clinical practice and we really want it to be applicable to our colleagues across the country and wider hopefully, in terms of what they can take to the bedside.
Dr. Rebecca Mathew: So, we haven’t provided hemodynamic targets, we didn’t provide specific lactate cut points or urine output cut points. We’ve told people to do what they do in clinical practice, and I think that’s the beauty of doing these pragmatic trials is hopefully people in other centers can see their own practice reflected in what was done in the clinical trial and it helps them take care of patients. I think what’ll be interesting as we move forward in terms of the work we’re doing in cardiogenic shock research is seeing what targets are helpful and what targets actually correlate with hard outcomes down the road. Does hemodynamic guided resuscitation make a difference at 30 days? Can we use lactate clearly as a marker in terms of resuscitation and change outcomes down the road? I think that is a huge area of shock that needs to be explored more, something that we’re interested in exploring more. Right now, we just don’t have the data to guide that, and so that’s what we tried to replicate in our protocol. I don’t know if Ben wants to add anything to that or if he feels like that aligned-
Dr. Benjamin Hibbert: Yeah, I agree with you totally. And I think it also speaks to the importance of blinding in a trial like this because obviously people knew the treatment assignments and they might behave differently. So, I’ll say it makes a lot of cardiac intensivists feel uncomfortable to know if their patients are on an inotrope, it just speaks volumes to how I think patients would get treated differently if people knew. And so that’s why we think it’s incredibly important one, to have a placebo control trial and two, to blind to make sure that ultimately we’re able to ascertain whether or not the inotrope trope is responsible. But Rebecca’s bang on, we really want this to reflect clinical practice how people treat their patient’s day to day.
Dr. Pooja Prasad: So, I’m going to take us to talking about lactate, which came up in the answers to the last question. But Dr. Hibbert, I have a clinic preceptor who always says that lactate is the troponin of the non-cardiac organs, not to the fact that lactate often is a reflection of recent but not current malperfusion. Just wanted to get your thoughts on what you think about the composite outcome of lactate being cleared within six hours versus 12 or even 24. Many patients even with restored profusion continue to have elevated lactates for hours to days. I’m curious how you decided on lactate clearing within six hours and what it might mean for the results if both placebo and treatment arm have either A, a high degree of continued elevated lactates or B, crossover to receiving mechanical circulatory support.
Dr. Benjamin Hibbert: Yeah, great question. So, this end point is born out of one part of people’s lack of comfort with a placebo control and then secondly its evidence based. So, when we were designing this study, both of the duration of treatment as well as the bailouts had to be in place to make sure that people felt comfortable randomizing their patients to a plausibility of placebo. And so, if patients end up on very high vasopressin doses, were unable to maintain their [inaudible], were unable to successfully resuscitate and if something bad happens and they have cardiac arrest, they’re out of the trial and they bail out to open label. And this is commonly done in trials of vasopressors and inotropes because otherwise no one would ever enroll with a patient if we just persisted until they had a bad outcome. The nice thing is with this trial is we essentially have 192 patients in the treatment arm from the DOREMI 1 trial.
Dr. Benjamin Hibbert: And so, Jeff Marbach, who actually trained with us and is starting at OHSU as a cardiac intensivist, he’s a great person to work with if you get a chance. He actually wrote a paper in the Journal of American Heart Association, which is a sub-analysis of the DOREMI trial. And so, we looked at what were predictors of mortality and specifically looked at lactate clearance and lactate clearance points was a predictor of mortality. And actually, when we looked at early lactate clearance, we had eight hours in that paper. It was the strongest predictor of mortality. It was stronger than the SCAI class, it was stronger than their age, whether they were an AMI or non-AMI heart failure or non-AMI cardiogenic shock presentation.
Dr. Benjamin Hibbert: It had an odds ratio of four if you hadn’t cleared your lactate by eight hours. And so, we elected to pick that because we felt that if by six hours patients hadn’t cleared their lactate and we anticipate more than half the patients will clear their lactate by six hours based on the data that we have in the treatment arm. If they hadn’t by six hours it was such a strong prognostic marker of adverse outcome that we felt it would be important to bail them out to open label and then the treating team can decide what to do.
Dr. Benjamin Hibbert: Again, ultimately we’ll have those rates in between the groups and we look at this all the time in the trial, blind the data, but we’ll look at it and we’ll know the rates and if ultimately the rate of an individual endpoint is driving it because all the patients have elevated lactate then we’ll have to review that as the trial’s conducted. I can tell you so far we’ve rolled over 10% of the trial, it’s going extremely well, and a lot of the patients aren’t end pointing. And I’ve looked after a lot of these patients myself and it’s fascinating how many of these patients get better knowing that half of them are getting [inaudible]. And so, I think there’s just going to be a lot to learn from this first placebo controlled trial and cardiogenic shock. But it was for basically investigator comfort or for treatment team comfort and its evidence based.
Dr. Benjamin Hibbert: We know that if they haven’t been successfully resuscitated they’re out. As for your last point, crossing over to mechanical circulatory support, I anticipate this to be extremely low. So, while we anticipate having centers in the United States, this will be a predominantly Canadian based trial. We don’t use a lot of MCS, and I must admit we’re pretty hawkish on the MCS data in Canada. And so, I don’t anticipate that you’re going to see a lot of patients early in their shock crossing over to MCS. When our patients do, usually they’ve been flogged pretty hard with vasopressors and inotropes before they cross over and most of the patients will be out of that 12-hour window before they get crossed over to MCS.
Dr. Nick Smith: That’s great. One of the comments you made about you already have 192 patients, cohort of patients to look at from the original DOREMI trial really segues nicely into my next question, which I’ll direct to you Dr. Matthew, which is that one of the pitfalls or I guess potential pitfalls, I don’t know that we see it all that commonly, but of dobutamine would be in either ischemic myocardium where you could have worsening demand ischemia and where dobutamine might actually make things worse, or just in somebody who is prone to ventricular arrhythmias and dobutamine could stir up arrhythmias in otherwise irritable myocardium.
Dr. Nick Smith: We’ve talked about how out of hospital cardiac arrest patients are excluded, but my understanding at least, and please correct me if I’m wrong, is the AMI cardiogenic shock is not excluded. So, will the patients in the study include post MI patients? And if not, why? And then for anyone coming in with heart failure, cardiogenic shock, I’m thinking specifically of a patient who’s coming with a new first presentation of heart failure, they could be ischemic, we just don’t know, are you leaving it up to providers or are you in any way looking to assess whether they have a degree of coronary artery disease that could be driving the presentation? So, I’ll ask you that.
Dr. Rebecca Mathew: Yeah, so awesome question and it’s always great to hear questions that us as a group of investigators discussed at length when we were putting the trial together, because it makes us feel like, okay, we’re hitting on practical aspects that people are going to be interested in. So, we talked about this a lot while we were running the first DOREMI and definitely while we were prepping for DOREMI 2. And so, we actually have randomization by AMI associated cardiogenic shock versus non-AMI associated cardiogenic shock. So hopefully that answers your first question that we absolutely agree. These are different populations, they have different morbidity and mortality, they’re different from a prognostic perspective. And I think research is really being focused on different phenotypes and etiologies of shock because they are different and so we need to explore them understanding those differences. So, we’ve tried to address that with DOREMI 2 as best as we can.
Dr. Rebecca Mathew: The other thing that’s sort of interesting is one of Dr. Hibbert’s MD PhD students actually finished his PhD and his MD, he’s in residency now. Dr. Jung actually did a sub paper which is already being published actually looking at AMI versus non-AMI presentations in the original cohort. And we actually looked at the effects of mil versus dob and we saw no difference in the AMI cohorts. We did actually try to look at that in retrospect from DOREMI and certainly in DOREMI 2. In the AMI patient who’s randomized, absolutely the physician at the bedside, if they’re nervous about dobutamine, totally can pick milrinone as their inotrope that they want the patient to versus placebo depending on what the randomized to. But that is up to the physician at the bedside. So, we never want to do anything to obstruct or impede what the physician wants to do.
Dr. Rebecca Mathew: And we completely understand that there is that nervousness about ischemic myocardium and tachyrhythmias and worsening ischemia. So that’s why we’ve crafted DOREMI 2 in the way that we did to try to address those concerns. There’s so many things about DOREMI 2 that I think set ourselves up for even more trials coming as a result of that trial. I think that’s the best research where you’re in the middle of doing a project or a clinical trial and you can already see the road ahead and the next two to three trials down the road. So, we’ll see what things show, but we definitely tried to address that with DOREMI 2, yeah.
Dr. Pooja Prasad: So, for our final question, I’ll ask both you Dr. Hibbert and Dr. Matthew to give us an update. It sounds like you’ve already started enrolling, enrolled 10% of the patients and we’re curious to get an idea when we can expect to see results. And also, if you have any predictions on what we might find.
Dr. Benjamin Hibbert: Yeah, no, the trial’s been solidly exceeding expectations. Now we’ve only opened up two sites. We’re going to be opening up more sites in the near future. We’ve enrolled 10% of the cohort in a little over five months and that’s including the first month when you’re rolling the trial out. So, I think pragmatically this is going to take us 30 to 40 months to complete. So probably three years to finish. This trial’s larger, so it’s mid 300 so it’s going to be not quite double the size of the original DOREMI trial. But that being said, we’re going to have more sites on board. More people are paying attention to this field of research now and so I think we’re going to get more people interested in enrolling. In terms of predictions, if you had to ask me when we started, my bias was that I thought I inotropes would be helpful in the early resuscitation. Lactate clearance, we all have that experience of starting milrinone and dobutamine and lactate clearance.
Dr. Benjamin Hibbert: We pat ourselves on the back and we go about rounding. What’s interesting since I’ve been looking after randomized patients is a lot of the patients are getting better and I know half those patients are on placebo. And so, it does make me wonder if optimizing the patient’s volume status, giving them a little bit of hemodynamics with a vasopressor might be the right thing. What’s also interesting is when we looked at DOREMI 1, a lot of critical events happen in the first day. It’s not surprising patients come to us very sick, and we know these medications have side effects. They do induce tachyrhythmia and nothing is worse for a sick heart than a resuscitation. And so, I think it’ll be really fascinating to see are we perhaps harming patients by initiating these therapies that they don’t necessarily need? And I think it’ll open the door if it is negative to either a more prolonged therapy or maybe we’ve just been doing it wrong all along.
Dr. Benjamin Hibbert: We do need to implement MCS earlier and stop fiddling around with the drugs and support them upfront and not get some of these toxicities. So, all of that to say is even in the first 40 patients, what I think is going to happen is changing. And I think that just speaks to how little we know about cardiac intensive care. I’m an interventional cardiologist. I know an awful lot because we have great evidence bases for some of the things we do in the [inaudible]. And then when I change rooms and I go and I work in our cardiac intensive care unit, I sit there and then we lick our finger, we put it in the air, and we do what we always did. And so, I think young people like you who are fully trained in cardiac ICU and eat, breathe, and sleep this stuff are going to change this field and going to move mortality because we’re going to get rid of the things that don’t work and we’re going to start implementing these things that work. So, I don’t know, is the short answer.
Dr. Nick Smith: Well now, credit to you both for changing the field and for all that you guys have done and for taking the time out this evening. This has been a real pleasure and we’re just so thankful.
Dr. Benjamin Hibbert: Thank you very much.
Dr. Rebecca Mathew: Yeah, it was great to chat and super exciting to see other cardiac ICU people coming through. This is a really, really exciting time for our field and we really get to shape it and make it our own. So, it’s just awesome.
Dr. Pooja Prasad: Thank you so much. It was so nice meeting both of you.
Dr. Rebecca Mathew: Bye.