Dr Christopher Cannon discusses the potential of Pragmatic Clinical Trials in our research armamentarium with Dr. Thomas Nero. They review the EVOLVE-MI trial for Early use of Evolocumab after Myocardial Infarction in detail and highlight the potential for future research.
Dr Christopher Cannon discusses the potential of Pragmatic Clinical Trials in our research armamentarium with Dr. Thomas Nero. They review the EVOLVE-MI trial for Early use of Evolocumab after Myocardial Infarction in detail and highlight the potential for future research.
Welcome to Future Pulse. Today I have the pleasure of speaking with Dr. Christopher Cannon. Dr. Cannon is the Director of Education at the Cardiovascular Innovation Division at the Brigham and Women's Hospital in Boston, Massachusetts. He is a professor of medicine at Harvard Medical School and senior physician at the Brigham. I'm sure he is well known to most of us and is as he is throughout the world for his work, which has included over a thousand papers, 18 textbooks, as well as principal investigators on over 20 multi-center clinical trials. He has been a thought leader in CV research for many years, and it is my honor to discuss with him today new paradigms in clinical trial research and specifically pragmatic research trials.
And the Evolve MI trial of early of Evolucimab, very early after myocardial infarction.
, we're at an inflection point here in cardiovascular research where we have a number of very effective agents , but it's often difficult to decide which therapies to [00:01:00] apply, when to do so.
And in which combinations. Do you think this is partially how we're modeling our research.
Chris: Well, it's a very good point. Sort of a good problem to have of having so many things that work in cardiology, but , it does get crowded and confusing as to what we're gonna offer, . , nonetheless, I think , in a trial. Testing, either a drug or a strategy. One does have to test that one strategy on a background of a standard guideline recommended practice.
And so I think in general, the trials of looking at one thing or another are reasonable. I suppose in the covid space, the recovery trial program that tested like eight or nine different covid medications was a wonderful example and continues to be one that we would strive for a pragmatic trial that can test a lot of different therapies.
They did start [00:02:00] adding things as they showed steroids or better, that became background therapy for then testing, , the, , inflammatory inhibitors , and other agents. So hopefully we can do similar things in cardiology to tackle the multitude of questions we have for our patients.
Tom: And certainly during that period of time, there were so many patients all at once. That we had a large database to work from and reapply our hypotheses and retest them in real time.
You were a very early adopter you were, approached for the, evolve MI trial before Covid. So what led you to looking into pragmatic trials as a way to solve some of these questions ?
Chris: Part of the goal with the pragmatic trials is to simplify the trial and make it then easier for all of us to enroll and participate in trials. There's a lot of regulatory paperwork that. Makes good sense early on in testing a brand new drug . We need to collect [00:03:00] every bit of information about any possible side effect.
But as we have, prior trials on a given therapy and certainly after it's approved, Then one should try to scale back all of the amount of information that's collected and the detail so we can focus on the big questions, . Currently to do any trial, you need a research coordinator and IRB and tons of paperwork and then the, probably the adverse.
Collection monitoring data, , entry into a separate database is probably the biggest time sink, and responsibility. So if you have approved drugs, you know largely the adverse event profile that one could. Back off a little bit, try and collect information through the electronic record where it's captured anyway, and use that.
Whereas all the trials in the United States largely had the usual same rules where they had to collect everything under [00:04:00] the sun. And all the trials are like four or 500 patients and basically have not been at all useful. So facilitating and matching. What's necessary to collect really then translates into bigger, , numbers of patients and more meaningful trials.
So I think that's , the main goal is to be able to do larger trials that can give better answers while preserving the key parts of safety tracking, but getting rid of some of the unnecessary ones.
Tom: Do you think that this should be included as a standard for most of our phase four trials, you know, there has been a big movement through FDA to having more tracking and follow up, close follow up after. After approval, and it seems like this is sort of a natural to expand what we can find out about these drugs and really dive into the data in a real world way that we're not able to do otherwise..
Chris: I think it is, and, [00:05:00] and I think you're right that the FDA is interested in this. They've given some guidance, but there aren't rules written down for sort of a, a middle level of, , monitoring. So that there are all the rules for regulatory submission of a new drug where you wanna collect all the details and , you'll identify, , strange and unexpected side effects that in retrospect you can understand, but you need the detail and scrutiny, but, After you've enrolled five or 10,000 patients, you've got a pretty good idea.
And so fda, I think said, you know, we really need to make a judgment as to whether we could move to a more limited monitoring scenario. then for doing the trial itself, there really needs to be a new set of rules that it's okay to do this. So in Covid, under the emergency, declarations, some of.
Came to be and certainly in the [00:06:00] United Kingdom. , but, , I think having that now for other trials where we wanna test different strategies of approved drugs, would be nice and we all wanna follow the rules and do things safely for our patients. , but trying to find that middle ground, and.
Be, allowed by the regulatory agencies and, , companies, if they're sponsoring a trial, wanna be sure they're not, short changing patient safety or things. So I think one of the conclusions we've come in developing this trial and other recent ones is that we do have to, , establish this new set of rules, , for pragmatic trials.
Tom: Is there something specific that you about acute coronary syndromes that you really think lends itself to this type of trial? Or do you think that we really can expand it to other approaches?
Chris: Well, both. I think it, this applies to everything, but [00:07:00] acute corner syndromes are, as in the name, acute and serious. And so Being able to enroll a good number of patients with new therapies and not to burdensome is important. , the doctors , and nurses and everyone else are focusing on caring for the patient,
, and they don't have time, frankly, to do a lot of the busy work that would be involved in some of the more detailed trials. So, , if we can simplify and make it easier for the clinical team to participate, then we'll get many more patients involved , and so it, it is a particularly good group of patients to do this in, but it would apply for many different areas.
Tom: I also think it helps that, , these patients are very high risk and they're more likely to have early events. And so we may be able to see a differentiation between these groups earlier, , just because of the nature of the patients that we're going to be working with.
Chris:
You're, you're quite right that you know the trials that enroll [00:08:00] patients in the first 24 hours have much higher event. Early on than those where we enrolled at the time of discharge. So a lot does happen in the first week or so. So facilitating early treatment with a simplified trial will be likely translate into more benefit for patients if the therapies do work.
Tom: So Elu lab has been available for clinically for a number of years.
Why not just start patients on this drug? , do you think there's a need to lower cholesterol by two to separate mechanisms?
Chris: Certainly the mantra of lower is better, has been born out now over and over and over, but in a longer term setting, , if we were allowed to prescribe what we thought was best, we probably would start. Prescribing this earlier. , but with cost issues, the insurance companies would limit us.
Dialing back almost 20 years to the prove it trial with statins. Obviously all the statins [00:09:00] were available at the time and we tested whether the high dose statin would be helpful and, , seeing the benefit in the trial, , years after we started, It is helpful to get, these data to say, okay, this is the amount of benefit that we could expect.
Rather than think, oh, I think it's probably better if we do X or Y. , so I think there will be a real benefit in having a, , trial that can quantify the benefit. We're assuming it, it's gonna be beneficial, but it may, , not make as much a difference as we anticipate. So we do need to do , the proper study to see..
Tom: , will you be tracking the LDL cholesterols and be able to differentiate between achieved LDL cholesterol and outcomes, , based on the size of the database that you're building here?
Chris: We'll certainly have all the LDLs that are collected over the multiple years , in the trial, and we'll have a sub-study where we systematically do it, , to make sure that we've got. You know, [00:10:00] collected with complete ascertain that people don't go missing. We all know what happens to the ldl. It goes way down.
, and there've been, , probably about six or seven trials with LDL as the primary endpoint in this acute setting. Usually three, 400 patients. And so it, it's really nice to see that, , almost 90% of people can get to the new lower. Goal for acute patients of less than 55 milligrams per deciliter for ldl, , within a month , .
So that type of big change in the LDL gives really a chance to show that this would provide an incremental benefit. So that's the missing piece though. We need the clinical events, so we'll have. Have a good idea on the ldl, but then now try and add in what happens, on clinical outcome.
Tom: And if you were going to bet on an LDL that you thought would be the perfect ldl, not the one that we're not the ones that are [00:11:00] the goals or what we put in from our guidelines, but , what's, what's your sweet spot? Where do you think , it's going to go?
Chris: All the studies are, it's just a straight linear relationship. The lower we go the better., at the AHA there was a presentation on the patients less than 20 in the Fourier trial and the extension, and they had the lowest event rate of everyone even. Bob Giuliano's original paper, less than 10, , to have single digits.
, whether you need to get that low in every single patient is, , a balance that, , you often need multiple drugs. And, , so the idea of matching how low you go to the risk of the patient is what the ESC guidelines beautiful have laid out. , and I do that clinically that, , if someone's stable coronary disease, they had an MI , eight years ago , then anything less than 70 is fine.
But, for the MI patients who want less than 55 and then if they have other high risk features, lower and lower, that notion of [00:12:00] matching the risk to how low we push, it will give incremental. Benefit, for that added effort of adding on multiple drugs to get down low.
Tom: One of the problems we have as clinicians is the granularity of what we do with the patient in front of us. Because for them, they always want to , have the best outcome, not just the, , good, for the population outcome. , , a lot of the conversations I'm having with my patients now are, well, what else can we add on?
Or what else should we add on? , it's interesting as you involve them , in that discussion and allowing them to help make that decision.
Chris: That's a wonderful discussion to have with patients that on the one hand they understand why we're obsessing over the different components of risk and when the patient understands the details. I think that's when it's really a collaboration on getting all the appropriate therapies. I think that's a wonderful.
Way that you're approaching patients to do that and then, follow the [00:13:00] trial data. Uh, sometimes that's a little ahead of the guidelines. , but if there's a good, rationale and trial basis , for pushing lower or doing other things, , then that's great to do it together with the patient.
Tom: Are there other clinical, endpoints that you're looking into, , for this trial? I know you said there's , A subpopulation that you're gonna be doing some testing on.
Chris: In this trial, , we've aimed to be pragmatic , to not have lots of other, unfortunately more mechanistic insights. I think we'll be focusing for this on some of the care delivery system thing. So we'll be asking patients, how does it work to have your medications mailed to you at home?
. And how is this trial? Say, , compared to doing other things, where you don't have to come in for visits, , so I think we'll learn a little bit more on healthcare delivery. And trial conduct, as [00:14:00] opposed to more detailed inflammatory markers and things.
Other trials will have more, stored databases and biomarkers and things it'll do a better job on, on that. So each trial has its limitations. , as we discussed this, many of the researchers of the steering committee were lamenting, oh, it'd be nice to have biomarkers or, , other factors, but.
If to make it simpler for the patients and participating investigative team, then some of those type things have to get cut out of this thing. So no trial is perfect
Tom: No, but you're absolutely correct. This is gonna be the paradigm that we're going to be working from in order to try to determine. Trial design In the future. , I think you should really be congratulated for stepping out and trying to get this done.
. Were there other limitations in the trial design that stood out to you and said, , it will work for this, but it won't work for these other kind of.
Chris: In trying to design a pragmatic trial, , we we're focusing on,[00:15:00] , the pragmatism. And so one of the things. That we're still actually exploring is whether, , we could get the drug delivery done through sort of the normal mechanisms that, , they would get a card and they'd go to the pharmacy and be able to just pick it up along with their other medications as opposed to have to get research supply and the coordinator has to bring it.
. On the back end of the trial, the holy grail is to be able to have passive collection of the information as opposed to having to have a study coordinator enter in extra information on each patient and, and call up every three months and gather.
Extra information and doing that electronically sounds easy, , but then making all the variables match and so that they can be pulled into a single database with, , a hundred different hospitals is a key, component of this.
So some of. [00:16:00] Participating hospitals here have done that in one of the covid trials. , , within , the, , English, , healthcare system. It's all one big gigantic system. So that can happen, , in Sweden that's doing this trial, they have the national database of all.
Things and they have coded endpoints with definitions. So that's really the goal is could we do that? Then , layer in a randomized study up front, but then all the rest of the information can be gathered, per usual care. So that really opens the door to being able to do more studies. So working on the architecture , of data collection and having it passively, , run into trial databases, from the electronic health records is probably the biggest area that we hope to evolve. And pun intended, actually, the, the name we chose, , is we're trying to evolve the medical care of acute coronary syndrome, but also we're trying to evolve, , trial [00:17:00] conduct.
And so it served as a nice two names, , to capture the goal , of the trial.
Tom: So it's, this is an open label, , trial design. , do you have any worries about, , patient retention , , and especially manipulation in the non-intervention arm?
Chris: Certainly the patients will know , and, , if they haven't been randomized to the, early PCSK nine inhibition, would they get it later? We anticipate that will happen from a trial point of view. It probably should happen, , for some patients, if they follow the current guidelines.
We do want to compare this to current guideline based strategy. Because the insurance companies are so tough, it happens really late that you have to prove on Hydrostat and Ezetimibe and the LDL still above 70, that then you're allowed to get it. , I think we don't want.
Half of the control arm to just get it beyond guideline. . Of course, for any [00:18:00] individual patient we. Let the clinicians do what they think is best for the patient. But that will be certainly the drop ins as that would be known in, in trial language would be an important factor.
We'll track over time, , if there's a high percentage of that, then that will. Decrease the difference between the two arms. And so , the trial response would be one would need more patients to be able to detect a difference between , a smaller LDL difference in the two arms.
Tom: , so did you have any difficulty in convincing the sponsors for this approach? , were there specific hurdles when you were trying to get this program together years ago?
Chris: You know, not really. I think this is sort of a natural next step for this field. They have sponsored a few of the, , LDL endpoint trials. So Evo packs was one of the first and. A beautiful imaging study, Hogans, that shows the evolution of the [00:19:00] plaque exactly as I imagine it. But they actually, Steve Nichols and colleagues, , have collected the data on the lipid core going down by, , a third or half, and then fibrotic, , remodeling of the plaque.
So a beautiful mechanistic study. Uh, so the. For the sponsor, this is then the next natural thing. So I think everyone's aligned that this is the right thing to do. Um, they're also aligned in wanting to be pragmatic. And one of the difficult things is that there aren't the written rules, uh, of how to do a pragmatic trial.
So then when the rubber hits the road and we're saying, how are we gonna collect the safety data? All they have are the strict rules for regulatory pathway trials , , and that's where I think this idea of trying to get new written rules that then everyone can follow , to do a safe trial, but trying to cut out some of the [00:20:00] excess burdens.
Tom: Looking at the imaging I think was extremely interesting. I'm actually gone one step beyond that and in our evolution of thinking over here, and we're looking at the inflammatory imaging on top of that, and especially the, , FAI.
Studies have been , promising , and we try to move away from using, , these secondary endpoints. . But I do think that we have to start moving towards things that are more specific and granular to the individual patients so that we can make a decision about these trials of how effective they're going to be early and we can move on or move forward even more quickly.
Chris: .
Yeah, and that has been a, big need in the field of what are the markers , I think the imaging is probably the best one, and the inflammatory component of this whole disease is really. Just being understood and being able to be better measured. , the concepts is, Peter Libby's been talking about for 20 years and then now we're getting clinical tools that we can, you know, [00:21:00] see and measure it.
, and then, , it suggested in CANTOS real potential benefit from anti-inflammatory therapies. So it's a whole fascinating area of investigation now and potential.
Tom: . Well, Dr. Cannon, thank you so much for being with us today. I, I can't thank you enough for all the work you've done to advance cardiovascular medicine and to help our patients.
And of course, thank you for taking the time out of your busy day to speak.
Chris: Well, thank you very much. It's a delight and it's a wonderful review of, of a great. The trial to help patients , and then help all of us do more trials to study other important things.
Tom: Thank you.