Circulation March 2, 2021 Issue

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.