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Circulation on the Run


Mar 1, 2021

This week, join author authors John J.V. McMurrary and Milton Packer, and Associate Editor as they discuss their Perspective article "How Should We Sequence the Treatments for Heart Failure and a Reduced Ejection Fraction? A Redefinition of Evidence-Based Medicine."

TRANSCRIPT BELOW

Dr. Carolyn Lam:

Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. We're your co-hosts. I'm Dr. Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore.

Dr. Greg Hundley:

And I'm Dr. Greg Hundley, associate editor, director of the Pauley Heart Center at VCU Health in Richmond, Virginia.

Dr. Carolyn Lam:

Greg, this feature discussion is going to knock you off your seat, because it did me. It's about treatment sequencing in HFrEF and discussing it with some luminaries on the field, Dr. John McMurray and Dr. Milton Packer. You are going to love it. I loved it. But I'm going to make you wait. How about you grab some coffee and let's start with some of the other papers in today's issue first.

Dr. Greg Hundley:

All right, Carolyn. How about if I go first? I'm going to start with a paper from Dr. Liam Brunham from the University of British Columbia. Well, Carolyn, the high density lipoprotein or HDL hypothesis of atherosclerosis has been challenged by clinical trials of cholesterol ester transfer protein, or CETP inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of HDL cholesterol, or HDL-C, declined drastically during sepsis. And this phenomenon is explained in part by the activity of CETP, a major determinant of plasma HDL-C levels. So Carolyn, these authors tested the hypothesis that genetic or pharmacologic inhibition of CETP would preserve HDL levels and decrease mortality in clinical cohorts in animal models of sepsis.

Dr. Carolyn Lam:

Huh. Interesting. And what did they find?

Dr. Greg Hundley:

Well, Carolyn, results from both the human UK Biobank and the mouse model experiments suggested that inhibiting CETP may preserve HDL levels and improve outcomes for individuals with sepsis.

Dr. Carolyn Lam:

Wow. So is this ready for clinical applications somehow?

Dr. Greg Hundley:

Well, Carolyn, two conclusions from this work. First, high density, lipoprotein cholesterol, a commonly used biomarker for cardiovascular risk assessment, may also predict risk of death from sepsis. And then second, cholesterol ester transfer protein inhibitors that have been tested in clinical trials of cardiovascular disease could be repurposed and studied in clinical trials of sepsis.

Dr. Carolyn Lam:

Ooh, exciting. Well, Greg, for my paper, I'm going to ask you a question. Have you ever thought about what the temporal changes in medical prevention and adverse outcomes are in patients with symptomatic peripheral artery disease after revascularization? Well, wait no longer. Our next paper addresses that. It's from Dr. Sogaard from Aalborg University Hospital in Denmark and colleagues who identified all patients with a first open surgical or endovascular revascularization procedure in the lower extremities or abdomen in Denmark from 2000 to 2016. And this is what they found.

Dr. Carolyn Lam:

First, the profile of patients with PAD who underwent lower extremity revascularization changed towards older age and a higher prevalence of comorbidity. Despite increases in age and co-morbidity, medical prevention of adverse events improved substantially over time, particularly in the first part of the study period and among patients who used medications chronically.

Dr. Carolyn Lam:

Now in contrast, initiating treatment after revascularization increased modestly among treatment-naive patients. Now concurrently, prognosis improved for almost all adverse outcomes in patients of both sexes, all age groups, and in all high-risk co-morbidities. In particular, the risks of myocardial infarction and cardiovascular death declined by more than 40%.

Dr. Greg Hundley:

Well, Carolyn, are there any other findings with clinical implications here?

Dr. Carolyn Lam:

Yes. So that was the good news earlier. But despite overall improvements, significant disparities remain. Less than 40% of treatment-naive patients initiated cardioprotective therapy after revascularization, underscoring the need for raising levels of awareness and education in the vascular community, general practitioners and patients of this. Major amputations also remained unchanged and thus more work is needed to understand relationships between the preventive measures, revascularization and amputation.

Dr. Greg Hundley:

Great summary, Carolyn. My next paper comes from Dr. Rachael Cordina from the Royal Prince Alfred Hospital, University of Sydney. Neurocognitive outcomes beyond childhood in people with a Fontan circulation are not well-defined. So the investigators here aim to study neurocognitive functioning in adolescents and adults with a Fontan circulation and associations with structural brain injury, brain volumetry and postnatal clinical factors.

Dr. Carolyn Lam:

Okay, you got our attention. What did they find, Greg?

Dr. Greg Hundley:

Thanks, Carolyn. So participants with a Fontan circulation, without a pre-existing major neurological disability, were prospectively recruited from the Australia and New Zealand Fontan registry. And the investigators found that neurocognitive impairment is common in adolescents and adults with a Fontan circulation and is associated with smaller grey and white matter brain volume. Understanding, therefore Carolyn, modifiable factors that contribute to brain injury to optimize neurocognitive function is paramount.

Dr. Carolyn Lam:

Indeed. Well, this next paper I want to talk about is the first detailed endothelial cell cysteine-S self-hydrome.

Dr. Greg Hundley:

Self? S self-hydrome? What is that, Carolyn?

Dr. Carolyn Lam:

Good. I needed to catch your attention. Let me tell you about it. So in vascular endothelial cells, cysteine metabolism by cystathionine gamma-lyase, or CSE, generates hydrogen sulfide- related sulfane sulfur compounds. And these exert their biological actions via cysteine-S self-hydration of target proteins. So the paper we're talking about today by Dr. Fleming from Goethe University in Germany and colleagues, they aimed to map the S self-hydrome, which is the spectrum of proteins targeted by this hydrogen sulfide-related sulfane sulfur compounds, or H2Sn, in human endothelial cells. And they did this using liquid chromatography and tandem mass spectrometry.

Dr. Carolyn Lam:

So here's what they found: vascular disease was associated with mark changes in the S self-hydration of endothelial cell proteins involved in mediating responses to flow. Integrins were most effected by S self-hydration and the modification of beta-3 integrin resulted in reshuffling of the intramolecular disulfite bonds to preserve its extended and open confirmation. Loss of beta-3 integrin self-hydration, on the other hand, inhibited endothelial cell adhesion, impaired mechanosensing and attenuated flow induced phase with dilation. Thus, short term H2Sn supplementation could improve vascular reactivity in humans, highlighting the potential of interfering with this possibly to treat vascular disease.

Dr. Greg Hundley:

Very nice, Carolyn. You know, just more from the world of hydrogen sulfide and endothelial function. Thanks so much. Well, the next paper I have comes to us from Dr. John McEvoy from Johns Hopkins University School of Medicine. So Carolyn, recent clinical guidelines support intensive blood pressure treatment targets. However, observational data suggests that excessive diastolic blood pressure lowering might increase the risk of myocardial infarction. Therefore reflecting, does a J or U-shaped relationship exist when we're following the treatment of diastolic blood pressure? So Carolyn, these authors analyzed 47,407 participants from five cohorts with a median age of 60 years. First to corroborate prior observational analysis, the authors used traditional statistical methods to test the shape of association between diastolic blood pressure and cardiovascular disease.

Dr. Carolyn Lam:

Okay. So was it J or U?

Dr. Greg Hundley:

Okay, Carolyn. So interesting, traditional observational analysis of the cohorts suggested a J-shaped association between diastolic blood pressure and myocardial infarction. However by contrast, linear MRI analyses demonstrated an adverse effect of increasing diastolic blood pressure increments on cardiovascular disease outcomes, including myocardial infarction. Furthermore non-linear MRI analyses found no evidence for a J-shaped relationship. Instead confirming that myocardial infarction risk decreases consistently per unit decrease in diastolic blood pressure, even among individuals with low values of baseline diastolic blood pressure. So Carolyn, in answer to you, no, the J or U-shaped curve does not exist.

Dr. Carolyn Lam:

I suppose depending which way you look at it. Very interesting. Well, let's finish up with what else is in today's issue. There's an AJ update by Dr. Elkin on COVID-19 at one year, the American Heart Association president reflect on the pandemic. A white paper by Dr. Zannad on challenges of cardio kidney composite outcomes in large scale clinical trials. A research letter by Dr. Kass on  the reduced right ventricular sarcomere contractility in HFpEF with severe obesity. Another research letter by Dr. Messas on the feasibility and performance of non-invasive ultrasound therapy in patients with severe symptomatic aortic valve stenosis. A first in human study.

Dr. Greg Hundley:

Right, Carolyn. So I've got an exchange of letters from Dr. Vazgiourakis  addressing a prior publication entitled Right Heart Dysfunction in COVID-19 Patients: Does Mechanical Ventilation Play an Additional Role? And then finally, an exchange of letters from Drs. Carrizales-Sepúlveda and Topalisky regarding the prior paper, The Spectrum of Cardiac Manifestations in COVID-19. Well, Carolyn, I'm really excited to get to that feature that you explained to us right at the beginning. Very exciting.

Dr. Carolyn Lam:

So am I. So am I. Thanks, Greg.

Dr. Carolyn Lam:

Wow. Today's feature discussion could not be more star-studded in my point of view. We are talking about the very, very hot topic of how do we sequence treatments in heart failure with reduced ejection fraction now? A really hot topic because just last year in 2020, we suddenly got a bonanza of positive trials and everybody's grappling with how to put it all together.

Dr. Carolyn Lam:

Now who better than the two authors I'm going to talk to today, Professor John McMurray from University of Glasgow and Professor Milton Packer from Baylor University Medical Center in Texas. So welcome both. John, Milton, I'm almost tripping over myself to talk about this because this is an amazing perspective piece. Everybody must get your hands on it and even look at the figure while you're listening to this. We're going to divide today's discussion into just three simple questions. Why do we need a new sequencing approach? How in the world do you come up with a new sequencing approach? Based on what? And finally, what is that new approach that you're both proposing? So maybe I'll start off with you, John. What's wrong with what we've been doing?

Dr. John McMurray:

So Carolyn, I think we've maybe neglected the fact that while we think of, for example, cancer as something that's incredibly urgent to diagnose and to treat as fast as possible, to give the patient all those life-saving therapies, we haven't had the same urgency in our treatment with heart failure. And our existing approaches, as you know, being largely one of start with the first treatment that was ever tested in the trial, up titrate to the pill dose, take your time, then on the second, third and so on. And of course, what that means is that it takes months for patients to be treated with all of the fantastic life-saving options that we have available for them. And we know that that's failing.

Dr. John McMurray:

We've seen from numerous registries, CHAMP registry in particular springs to mind, where that's simply not happening. It's probably taking too long. It's too complicated for both the doctor and the patient, and we need to change it. And I suppose Milton will tell you his view, but I think my view and I think his as well, was that the SGLT2 inhibitor story really brought this question, I think, to the fore because here is our fourth life-saving drug that if we do things the same way might not get started for six months. And we really felt that we need to rethink what we're doing. Milton, I'm sure, will say whether he agrees with that. But I think that was sort of where the starting point was.

Dr. Carolyn Lam:

Great. But if I could interject a bit, so now we're talking about that left side of the panel, where in your beautiful article where you're showing, we start with ACE inhibitors and ARBs, and then go on to beta blockers and mineralocorticoid receptor antagonists, and so on. I would love to know, and Milton I'm sure you'll add, is it the sequence that's wrong? Or is it really just the timing? Or the fact that we're just all too lazy? What do you say to people who go, "But that's how the trials were done." Especially because you guys both led those amazing trials of ARNIs and SGLT2 inhibitors. It's just awesome.

Dr. Milton Packer:

So Carolyn, what's really amazing is that everyone assumes that that's how the trials were done. But two things, one, just because we did things in a certain way, developed things in a certain way, doesn't mean we have to prescribe them in a certain way. I mean, we developed digitalis before all of them and so does that mean we need to use digitalis in everyone? But a lot of the early trials, all the patients were, or most of the patients were, on cardiac glycosides.

Dr. Milton Packer:

There are four things that we've learned from the large-scale clinical trials. One is the order of drugs does not matter with respect to efficacy. The beta blockers work the same whether people are getting ACE inhibitors or not, MRAs are not effected by background therapy. Neither is neprilysin inhibitors. They work pretty much the same regardless of background therapy, so you don't have to sequence them in the order in which they were developed.

Dr. Milton Packer:

Two is low doses, low starting doses of these drugs seem to work amazingly well, perhaps surprisingly well. And the third thing is that they work very early. So in a lot of the clinical trials, nearly all the trials that were carried out, there was a meaningful separation of the curves and in effect size in the first 30 days of all of these trials. And in many of the trials, in the first 30 days, patients were still on the starting dose. Hadn't been uptitrated.

Dr. Milton Packer:

The last point is that these drugs can influence each other's safety profiles. So the result of all of this was for us to rethink what the sequence should be based not on how the drugs were developed, but how they might be most logically used with respect to relative efficacy, safety and ease of use.

Dr. John McMurray:

So, Carolyn, to go back to your question then is sort of what Milton is saying is that it's a bit of both of the things you asked about. It is about timing, but it's also about the order of the drug. And that last point Milton made is very important about the potential synergies in terms of making it easier to use treatments, but timing is critically important as well. I mean, we do tend in the conventional approach to therapy recommended in the guidelines to perhaps spend too much time trying to reach that target dose, and then doing that before moving on to the second drug. So again as Milton pointed out, if you're getting early benefit from all of these treatments, fundamentally what you want is as many of these treatments started as quickly as possible as you can do safely. And that may be facilitated by some of the synergies between treatments as we, I think, rather provocatively suggested in the new algorithm, might even be possible to start two treatments at once.

Dr. Carolyn Lam:

Okay. Now I know everybody's really, really wondering what that new algorithm is, but I'm going to lengthen the pain a little bit more because this is critically important. You've already started discussing the how did you come up with an algorithm. It seems a lot of, yeah, very reasonable approaches, but could you give us specific examples of actual scientific interrogation of the data from the trials that you've led, frankly, to show us these points, that maybe support that we can come up with a reasonable new approach? Those points that Milton very rightly put, the treatment benefit of each class is independent. Give us some examples of that. The dose issue, the side effects, how one could help in that too. Could you give us some examples?

Dr. Milton Packer:

Oh, my God. So let me say that there's so many pieces of evidence and please read the article. We try to summarize as much of them as possible. But in all of the major clinical trials, there was a separation that occurs within 30 days. That's true across every single major trial. Anyone who thinks that the treatment effects of these drugs are delayed, that it takes months to evolve, we're getting statistical significance within two to four weeks across all of the drugs.

Dr. Milton Packer:

Second is, in many of the trials, for example, COPERNICUS trial with carvedilol, the trials with MRAs, even the trials with ACE inhibitors, during that first 30 days when the curves were separating, patients hadn't been uptitrated. They started on low doses and remained on relatively low doses and the curves were separating. So we knew that the drugs had early effects at low doses, low starting doses. And we also have randomized trials that really tell us that if you go to high doses for some of these drugs, you get a little bit more benefit, but you don't get as much benefit as starting another drug with a different mechanism at a low dose.

Dr. Milton Packer:

And lastly, we know that some of these drugs actually prevent the side effects of others. There's evidence that neprilysin inhibitors and SGLT2 inhibitors mitigate the hyperkalemia produced by spironolactone and aplerno. So these are just a few examples.

Dr. John McMurray:

Sorry, Carolyn. To add a couple more, we obviously know that the treatments work independently. We primarily knew that from subgroup analyses, but also from trials like RALES for example, where spironolactone was tested in addition to an ACE inhibitor, but very, very few patients were on a beta blocker. Subsequently we tested different a MRA in patients who were taking both an ACE inhibitor and a beta blocker, and the benefit was essentially the same. And of course, our very first trial with an ACE inhibitor, the CONSENSUS trial, was actually done in a population where more than half of the patients were on a very large dose of an MRA. So you can sort of put all the trials together in a type of jigsaw and figure out that these drugs all clearly work independently.

Dr. John McMurray:

And then maybe the only other thing I would mention, because it's perhaps relevant to the new algorithm, is that we do have another key trial, which is, a trial I think often forgotten about, the CIBIS III, which was a study that tested whether or not you could start treatment with either a beta blocker or with and ACE inhibitor in patients with HFrEF, showing that you could start with a beta blocker in patients who had not yet received an ACE inhibitor and do that safely and efficaciously. So there's a lot of material out there that you can sort of put together to answer all of these questions.

Dr. Carolyn Lam:

Great. And now drum roll. Okay. What is the new algorithm? John, you want to introduce it? Or Milton? Up to you.

Dr. Milton Packer:

John can start. That's fine.

Dr. Carolyn Lam:

Well, which one, Carolyn? I suppose the one in the Circulation article is a three-step algorithm. It starts with the combination of a beta blocker, based as I mentioned, so there's three plus an SGLT2 inhibitor. So again, thinking about synergies, thinking about tolerability, thinking about size of effect and thinking about repetity of onset of benefit. So I think most of us would agree, beta blockers are incredibly effective treatments, life-saving treatments, reduce the risk of sudden death. We know that you can start a beta blocker safely as first-line therapy. We do know that there may be more intolerance in patients who are volume overloaded. So why not give a treatment that has a modest, initial diarrhetic effect when you're starting the beta blocker? In other words, the SGLT2 inhibitor. SGLT2 inhibitors work extremely quickly. There's no dose up titration needed. So they seem like the perfect combination to start with.

Dr. Carolyn Lam:

In step two, we suggested moving then to sacubitril valsartan, which in itself is two more drugs combination of an angiotensin receptor blocker and their prolines inhibitor. And then there's the third and final step. We suggested using a mineralocorticoid receptor antagonist. But Milton and I have had a lot of discussion about this. I think we're not saying that all those are necessarily the three steps for all patients. There may be different approaches in different people depending on patient's characteristics. But really the point here was, the provocative statement was we should be able to do this quickly in all patients. And this in fact was an approach to get all four of those drugs started potentially within four weeks.

Dr. Milton Packer:

So Carolyn, the mantra here, our motto going forwards, is four drugs in four weeks.

Dr. Carolyn Lam:

Okay.

Dr. Milton Packer:

An angiotensin receptor blocker, a beta blocker, an MRA, an SGLT2 inhibitor. Four drugs in four weeks. And if you're going to start all four drugs in four weeks, in all honesty, the order probably doesn't matter that much. John and I happen to think that if you have to define a first step, a combination of a beta blocker and an SGLT2 inhibitor simultaneously as step one makes a lot of sense. And then you can follow up with sacubitril valsartan and an MRA.

Dr. Milton Packer:

But here's the thing that's really important: do not take months to follow up. What we're proposing in this algorithm is you start a beta blocker and an SGLT2 inhibitor on day one, and you then follow through with sacubitril valsartan and an MRA within the next couple of weeks. But here's what's really important and we really need to emphasize this: this is a algorithm that assumes that someone's not on any of these drugs already. And of course, most of these patients are taking some of these drugs already. But the other thing that's really important is that we're also assuming that physicians are being very meticulous about background use of diuretics, so that patients really have to be maintained in a clinically euvolemic state in order to make this algorithm work.

Dr. Carolyn Lam:

Okay, well, I'm picking myself off the floor because it certainly was provocative. I love it. I love it for that. It's the first time I've ever seen any algorithm start with a beta blocker and SGLT2 inhibitor. You first go, "Where's the ACE and how come the new kid on the block is right on top?" So I really like that because it must challenge our current thinking. In other words, if we just look at the data for what it is, let's see how we could think it over. So salute you for that. But let me just press on a little bit. So four drugs in four weeks. That's really great. Are there any particular patients you may say the ARNIs come on top or the MRAs? Specific situations or...?

Dr. Milton Packer:

Well, Carolyn, as John has already said, the physicians need to understand the principles, but the application of those principles have to be individualized. So if a patient has a borderline blood pressure, you would probably be well advised to put the MRA before sacubitril valsartan. Depending on renal function, you may decide to advocate one drug a little bit earlier or preferentially compared to another. There are hundreds of individualized nuances, but to get tied up in these is to miss the point of our paper. The point of our paper is that we need to do things quickly... Four drugs, four weeks... And we need to not rely on our historical testing in order to determine the optimal sequence. If you embrace those conclusions, then patients and physicians can individualize their care to the greatest optimal degree. But our current approach, which is a historically-driven algorithm that takes six months to execute, it doesn't work.

Dr. John McMurray:

Carolyn, we obviously did give a lot of thought to the initial treatments, and we did realize that it would potentially be a surprise to people. But just to reiterate, I don't think there's much debate about the incredible benefits of beta blockers, the size of that benefit. We know that the benefit is apparent within 30 days. So Milton and we had Henry Krum's very nice paper about that in JAMA from the COPERNICUS trial, but we're seen it in the other trials. You know that SGLT2 inhibitors have had early benefit. You think about these two drugs being used in a newly presenting patient with HFrEF, probably don't even need to do any electrolyte monitoring, provided your patients not volume overloaded or recently decompensated. That patient's very unlikely to have any significant intolerance to these two treatments.

Dr. John McMurray:

They don't, in those sorts of patients, substantially reduced blood pressure in either drug, beta blockers certainly don't affect kidney function. SGLT2 inhibitors have minimal effect on kidney function. If your GFR is relatively normal, you probably don't even need to check it. And of course, there's no effect on potassium. So in terms of getting two treatments onboard quickly that will have a rapid benefit, are likely to be well-tolerated in the type of patient that we just described, and where they might have monitoring necessary is minimal, then this seemed to be the best option. And as Milton said thereafter, it's maybe less important what order you do it in as opposed to the speed with which you do it. And you're right, you would definitely probably tailor this approach according to the patient characteristics, but this was a general starting point to stimulate debate, which it seems to have done.

Dr. Milton Packer:

So Carolyn, there's something important. If you believe in what we've proposed, then at the end of four weeks, every patient with heart failure and reduced ejection fraction would be on low starting doses or four foundational drugs. Our estimate is if doing that would provide them with a substantial benefit, maybe 70, 75% of the benefit of bringing all of those doses to target doses. And if you can do that, you can do all four drugs at starting doses at four weeks and provide that magnitude of benefit really quickly? That has a big impact on patients. And that has a big impact on public health.

Dr. Carolyn Lam:

Wow. Just thank you so much for igniting this debate. I wish we could go on forever. I just had to share that when we editors looked at this paper, it did spur a very robust debate. But as you can see, we're publishing it as you've proposed it because we do see where you're coming from. It is very interesting. And I just want to reiterate what you both just said, to listeners out there, remember this is referring to a patient who is compensated. Diuretics are still part of it. Remember that the key message is to get everyone on the four foundational therapies within four weeks. And I just love the way you pushed the boundaries with this. Really, really appreciate it. Milton, you look like you want to say something else. If you'd like closing words, I'd love to...

Dr. Milton Packer:

We really thank Circulation for having the courage to do this. And please understand, John and I strongly feel that this is the start of a debate. This is the start of a discussion. This algorithm is a proposal to get people to start thinking differently. This is not the final word on the subject by far. We think this is the beginning of a very important discourse that will evolve over the next year or more. And we just wanted to remind people what the clinical trial evidence actually shows about these drugs, because we think it has been frequently misunderstood much to the detriment of patients with heart failure.

Dr. Carolyn Lam:

Yes. And John, any last words?

Dr. John McMurray:

I would go back to where I started, Carolyn. In a way, what's important here is to inject a sense of urgency back into the way in which we treat patients with heart failure and reduced ejection fraction. It deserves that sense of urgency, as I mentioned that, for example, cancer does. And also thank you for summarizing, I think, what we tried to get across absolutely accurately.

Dr. Carolyn Lam:

Okay. So John, Milton, so far I take it. I take your points well, but as a practitioner, what I would do, frankly, is if I have a patient that I'm starting a beta blocker and an SGLT2 inhibitor, I would surely just start an ACE inhibitor perhaps, or ARNI, at the same time. I don't see why I need to delay it. How about that? Even faster?

Dr. John McMurray:

Okay, well, I'll let Milton answer the faster, but I would say one thing, Carolyn, the new algorithm doesn't mention ACE inhibitors or angiotensin receptor blockers as a monotherapy. Because I think those days are gone. I really do think that we shouldn't go through that cycle of starting a RAS blocker, uptitrating it, then switching to an ARNI because that's a waste of time. You're delaying the introduction of life-saving therapy. And this is the whole point to, again, get that sense of urgency across in implementing all of these treatments as quickly as possible.

Dr. Milton Packer:

And Carolyn, if you want to go faster, that would be fine. Maybe we shouldn't have proposed four drugs in four weeks. We should have proposed four drugs in four days. But Carolyn, I think that changing the way people think is a gradual process. Perhaps four drugs in four weeks is a good starting point. If everyone feels comfortable with that and understands why we are proposing that, then in another six months or so, Circulation can invite John and I to come back and propose four drugs in four days. But let's see what happens.

Dr. Carolyn Lam:

Kudos. Thank you so much. Well, thank you once again, John and Milton. That was an incredible discussion. A beautiful paper.

Dr. Carolyn Lam:

Thank you so much, listeners. I'm sure you enjoyed that as much as I have or probably more. But thank you and please don't forget to tune in again next week. From Greg and I, here's Circulation on the Run.

Dr. Greg Hundley

This program is copyright of the American Heart Association, 2021.