CVM Grand Rounds 11/5/2025: Mark Petrie

Transcript

• 00:01Professor Petrie will teach us
• 00:03today.
• 00:05So,
• 00:06first and foremost, just to
• 00:07remind everyone,
• 00:09welcome,
• 00:10among I think we have
• 00:11I've been told eight
• 00:13watch parties happening.
• 00:15Hopefully, you received the food.
• 00:16And,
• 00:18Mark, that's because we have
• 00:19a a a very,
• 00:21committed faculty across many different,
• 00:24hospital sites, and so we've
• 00:26tried to bring the the
• 00:27grand rounds to them, so
• 00:28that they don't have to
• 00:29get in the car and
• 00:30spend a lot of windshield
• 00:31time.
• 00:33And,
• 00:34and so,
• 00:35welcome.
• 00:36Let's go ahead and just
• 00:37a few reminders.
• 00:38Please sign up for CME
• 00:40activities,
• 00:41for five four three three
• 00:43six.
• 00:45Put that into your phone,
• 00:46you'll get your activity.
• 00:47Just a reminder of what's
• 00:49coming up next, we have
• 00:50one of our, I think,
• 00:51our third,
• 00:53case conference, this one on
• 00:54electrophysiology
• 00:55led by Gabriela.
• 00:57To to date, the there's
• 00:59a a tremendous,
• 01:03you know, I think,
• 01:05really, we're very so excited
• 01:07about the quality of those
• 01:08case conferences and the leadership
• 01:10of the fellows in that.
• 01:11So I,
• 01:12really wanna thank,
• 01:14our teams and our faculty
• 01:15and fellows for working together,
• 01:16and this has been a
• 01:17tremendous success.
• 01:19The next week is we
• 01:20have our,
• 01:22Giants in Cardiovascular Medicine series,
• 01:24recognizing Barry Zarrad and a
• 01:26full day
• 01:27of,
• 01:28of,
• 01:29a cardiovascular imaging symposium.
• 01:33This one, because of the
• 01:35size,
• 01:36and the location,
• 01:37will be held in the
• 01:38Park Street Auditorium. So that's
• 01:40where the rest of the
• 01:40symposium will will take place
• 01:42that day.
• 01:43I believe, Al, that starts
• 01:45at eight AM on on,
• 01:47the nineteenth, and it goes
• 01:48through the day with the
• 01:50the noon conference being a
• 01:51grand rounds, led by Todd
• 01:53Vilnius. And then we have
• 01:54a a
• 01:55subsequent, case conference led by
• 01:57our fellows. So Lindsay will
• 01:58be on the hook,
• 02:00with Jacob. So a lot
• 02:02coming up.
• 02:03These are these are disclosures,
• 02:06and, just a free a
• 02:07few brief notes,
• 02:10about,
• 02:11professor Petrie here,
• 02:13who
• 02:14is a rock star and
• 02:15one of my good friends
• 02:16and,
• 02:17that I've made
• 02:19through,
• 02:20our travels,
• 02:21in the world of of
• 02:21clinical investigation. So,
• 02:24Mark, just to briefly,
• 02:27provide you a summary, trained
• 02:29in Edinburgh.
• 02:30He's a Glaswegian,
• 02:32I guess, now. Is that
• 02:33right? How you say it?
• 02:34I don't know. You'll tell
• 02:35me how.
• 02:36And, and,
• 02:38he,
• 02:40is, someone who has had
• 02:42a huge impact on our
• 02:43day to day practice.
• 02:45There is,
• 02:46not a,
• 02:49a a medication we currently
• 02:51use
• 02:52actively for heart failure
• 02:54that,
• 02:55he and his team have
• 02:56not had an important part
• 02:58in positioning,
• 03:01with data,
• 03:02for its use. And I
• 03:04and that that's a it's
• 03:05a lot to say, but,
• 03:06you know, you can run
• 03:07down,
• 03:08his impact, his publications, his
• 03:10roles,
• 03:12in expanding our understanding of
• 03:14vestibule two inhibitions
• 03:15in clinical medicine, particularly cardiovascular
• 03:17medicine,
• 03:19in work that, he and
• 03:21I have done together,
• 03:23in in RAS inhibition with,
• 03:25both
• 03:26ARBs and then now ARNI's,
• 03:29in turn with aldosterone and
• 03:31antagonism,
• 03:32and most recently,
• 03:34of an increasing focus on,
• 03:36the cardiometabolic
• 03:37kidney access and work that
• 03:39he's done,
• 03:40in, in the,
• 03:43GLP one space, that I'm
• 03:45sure he's gonna teach us
• 03:47about. He's also had an
• 03:48important role in the in
• 03:50how we conduct the kind
• 03:52of clinical trials
• 03:53that have that make this
• 03:54impact on our guidelines and
• 03:56our day to day practice.
• 03:58A tremendous citizen of the
• 04:00world,
• 04:01in terms of cardiology clinical
• 04:02trials,
• 04:03serving in in, countless roles,
• 04:07chairing as well as a
• 04:08member of,
• 04:09events committees, of executive committees,
• 04:12of design committees,
• 04:14and having a,
• 04:16not only a focus
• 04:18on,
• 04:18on pharmacological
• 04:20interventions,
• 04:21but also in terms of,
• 04:23procedural,
• 04:26and implementation work in the
• 04:27field. He has been
• 04:29a leader in the European
• 04:31Society of Cardiology,
• 04:32helping to develop guidelines for
• 04:34cardio oncology just to name
• 04:36a few,
• 04:37heart failure with preserved ejection
• 04:39fraction,
• 04:40and others. And so, really,
• 04:42truly an exciting time for
• 04:44me personally. I've known him
• 04:45for probably twenty years plus.
• 04:48I think our first paper
• 04:49together was maybe fifteen years
• 04:51ago,
• 04:52on a dataset that we
• 04:53we helped create with his
• 04:54colleague John McMurray,
• 04:56in the nineteen nineties.
• 04:58And, and so it's just
• 04:59been wonderful
• 05:00to, to take this journey
• 05:02with Mark and see how
• 05:03much he's accomplished, and thanks,
• 05:05thanks for being here with
• 05:06us so much.
• 05:14Yeah. Yeah. I'll turn it
• 05:15on. So, again, Eric, thank
• 05:17you, first of all, for
• 05:18inviting me here. It's an
• 05:19absolute honor and a privilege
• 05:21to be here, and I
• 05:22think all of you should
• 05:23realize what a fantastic
• 05:25setup you have. I've,
• 05:28seen Yale functioning from afar
• 05:30for a long time, but
• 05:31today meeting,
• 05:32people in the department has
• 05:33been, fascinating. So I hope
• 05:35you enjoy your time here.
• 05:36It's obviously a real
• 05:38privilege and an honor, and
• 05:39I feel humbled to be
• 05:40here.
• 05:42So what I'm gonna do
• 05:43is I'm gonna look forward,
• 05:45not back. So some of
• 05:46the things Eric's talked about,
• 05:48I'm not gonna go into
• 05:49detail. So hopefully,
• 05:50I'm gonna interest you and
• 05:52entice you about things which
• 05:53are currently happening
• 05:55or are going to happen.
• 05:56So, and I also a
• 05:58disclaimer.
• 05:59First of all, I speak
• 06:00Scottish and not English, so
• 06:02I have to apologize for
• 06:03for the accent. So please,
• 06:05throw tomatoes or tomatoes at
• 06:07me if there's a if
• 06:08there's a
• 06:09problem.
• 06:11You know, secondly,
• 06:12I have to confess that
• 06:14although I am here as
• 06:16a kind of researcher academic,
• 06:18I started my career very
• 06:19much as a clinician. So
• 06:21I started off my attending
• 06:23consultant job
• 06:24setting up a PCI, primary
• 06:26PCI, wrote out as an
• 06:27interventional cardiologist.
• 06:29I was director of a
• 06:30vaginal transplant program at the
• 06:31same time and run a
• 06:32lot of heart failure services
• 06:34in clinics. So I'm a
• 06:35really clinician
• 06:36turned researcher
• 06:38rather than anything else, but
• 06:39I think what we share,
• 06:41Eric, is a common,
• 06:43feeling about cardiology that
• 06:46all of us every day
• 06:47see patients and the clinical
• 06:49questions come out of those
• 06:50interactions
• 06:51with patients and really demand
• 06:53research.
• 06:54I think most people involved
• 06:55in cardiology or cardiovascular
• 06:57medicine
• 06:58realize as they progress that
• 07:00really it's our job every
• 07:01day to embed research along
• 07:04with clinical practice. And the
• 07:06ethos that we have is
• 07:07that every single patient should
• 07:08be in a registry or
• 07:09a trial or certainly be
• 07:11part of understanding
• 07:13the pathophysiology,
• 07:14natural history, and treatment of
• 07:15cardiovascular
• 07:16conditions. So I know at
• 07:18Yale, you're at the forefront
• 07:19of these things, but all
• 07:21of us, I think, have
• 07:21a we're all required to
• 07:24do research alongside
• 07:26our day to day lives.
• 07:29So
• 07:29probably one of the hot
• 07:31topics at the moment, I'm
• 07:32sorry for the they're almost
• 07:34a pun, but not quite,
• 07:35is inflammation and cardiovascular disease.
• 07:38So,
• 07:39one of the,
• 07:40conditions that I heard about
• 07:42in audiences for many years
• 07:44was this narrative which, several
• 07:47people around the world
• 07:48drew us towards, which is
• 07:50inflammation
• 07:51driving HFpEF.
• 07:53Obviously, people like Paul Ridker,
• 07:56Peter Libby has spent a
• 07:57lot of time talking about
• 07:57inflammation and coronary heart disease,
• 07:59but in the heart failure
• 08:01world, we've heard all about
• 08:02inflammation and HFpEF. And
• 08:04the narrative and this is
• 08:05a hypothesis and a narrative.
• 08:06This is not necessarily true,
• 08:08but we hear that comorbidities
• 08:10cause inflammation,
• 08:12inflammation in the form of
• 08:13things like the various cytokines,
• 08:16have effects, on blood vessels
• 08:18around the body,
• 08:20particularly focused on the myocardium
• 08:22and the microvascular
• 08:23of myocardium
• 08:24having knock on effects to
• 08:25myocardial problems,
• 08:28fibrosis, hypertrophy,
• 08:30cell death, these sorts of
• 08:31things are then causing HFpEF.
• 08:33So we've heard of this
• 08:34for fifteen, twenty years, and
• 08:36I've been fascinated about this,
• 08:38but there's not been a
• 08:39lot of real data behind
• 08:40it. Of course, even more
• 08:42recently, things like the epicardial
• 08:44adipose tissue, the fat, like,
• 08:46around the heart being a
• 08:48having a paracrine function and
• 08:50driving, the myocardial abnormalities has
• 08:52also,
• 08:53been a major feature of
• 08:55lots of presentations.
• 08:57So
• 08:58this whole area is now
• 08:59fascinating, and this inflammation of
• 09:01cardiovascular disease is will be
• 09:03unavoidable for all of us
• 09:04here to try and understand.
• 09:07I have been educated and
• 09:09I actually did an undergraduate,
• 09:11immunology degree by chance,
• 09:13earlier in my career. But
• 09:15working with Paul Ridgkar, who
• 09:16I now work with every
• 09:17search, every week,
• 09:19he's now drawn us towards
• 09:21the NLRP three inflammasome,
• 09:23which
• 09:24even five years ago, I
• 09:25thought I wouldn't be standing
• 09:26here talking about inflammation, massive
• 09:28word, but this does seem
• 09:29to be crucially important.
• 09:31What happens,
• 09:32in the the disease states
• 09:34is that n r p
• 09:35three inflammasome is activated.
• 09:37We have interleukin one beta
• 09:38is is,
• 09:40activated by by this inflammasome.
• 09:42This leads on to IL
• 09:43six actions, and IL six
• 09:45then stimulates
• 09:46hepatic production of CRP
• 09:48as well as many, many
• 09:49other things IL six does.
• 09:51I could talk about this
• 09:51for hours, but I'm gonna
• 09:52give a relatively high level
• 09:54talk today, so not too
• 09:55much detail. But, certainly, the
• 09:57first thing to talk about
• 09:58is canakinumab,
• 09:59and this, was
• 10:01investigated in the CANTOS trial
• 10:03by Paul Ridker and colleagues.
• 10:05This is not a heart
• 10:06failure trial. This is a
• 10:07trial on people with prior
• 10:09myocardial infarction, so ten thousand
• 10:11people with prior MI and
• 10:13elevated CRP.
• 10:14And the primary endpoint, was
• 10:16a MACE endpoint cardiovascular death,
• 10:18MI and stroke, which was
• 10:19slightly reduced.
• 10:21You might remember there was
• 10:22slight increase in death due
• 10:23to infections and a decrease
• 10:25in death due to cancer.
• 10:26So interesting, but didn't really
• 10:28result in massive prescription.
• 10:30But really, one of the
• 10:31fascinating things was the finding
• 10:33of looking at heart failure
• 10:35events in Cantos,
• 10:36and there was a dose
• 10:38dependent reduction in heart failure
• 10:39events with IL one beta
• 10:41inhibition with canakinumab in Cantos.
• 10:44So this alerted the world
• 10:45that maybe there was a
• 10:46therapeutic,
• 10:48strategy to be tested,
• 10:49in people with heart failure.
• 10:52A further analysis,
• 10:53that that Paul's team did
• 10:55was looking at people who
• 10:56achieved
• 10:57a lower CRP in CANTOS,
• 10:59and people that achieved the
• 11:00lower CRP
• 11:02had a pretty big reduction
• 11:03in heart failure events. Seeing
• 11:05that there wasn't very many
• 11:06events in these trials, event
• 11:07date was quite low. So
• 11:08this is not definitive data.
• 11:11The other thing that Cantos
• 11:12did was bring us towards
• 11:14IL six, as a potential
• 11:16major player in this area.
• 11:17And if we looked at
• 11:18the turtles of IL six,
• 11:20people with higher IL six
• 11:21levels did, particularly badly in
• 11:23terms of heart failure events
• 11:25in Cantos.
• 11:26There's been explosion of interest
• 11:28in looking at IL six
• 11:29across cardiovascular disease and particularly
• 11:31looking at heart failure.
• 11:33And in primary care, in
• 11:34the community dwellers, we certainly
• 11:36know that IL six is
• 11:37associated with incident,
• 11:39heart failure.
• 11:40It's also associated with incident
• 11:41death as well. So certainly
• 11:43IL six goes alongside
• 11:45poor outcomes in the community.
• 11:48We also, looked at IL
• 11:50six and, outcomes, heart failure
• 11:52outcomes in hospitalized heart failure
• 11:53people, and it seemed to
• 11:54bear true there as well.
• 11:56So Barry Borlaug, again, who's
• 11:59another close colleague, has looked
• 12:01at several NIH trials and,
• 12:02again, has found an association
• 12:04between higher IL six levels,
• 12:06and,
• 12:07health status or quality of
• 12:08life.
• 12:09But of course, all of
• 12:10us have been,
• 12:11cardiologists are brought up to
• 12:13know that association
• 12:14is not causation. So this
• 12:16is an association
• 12:17with bad outcomes of poor
• 12:18health status.
• 12:20So, what happened then was,
• 12:23a drug was basically bought
• 12:25by Novo Nordisk, called ziltivekimab.
• 12:28This is a once monthly
• 12:30subcutaneous,
• 12:31monoclonal antibody to the IL-six
• 12:33ligand.
• 12:35So people,
• 12:37whenever there's a new asset
• 12:38bought, people scratch their heads
• 12:39and think what to do
• 12:40with it.
• 12:41So the data here that's
• 12:43there was a basis of
• 12:44of Novo Nordisk buying this
• 12:45drug was not a heart
• 12:46failure,
• 12:47data not heart failure data
• 12:48or even cardiovascular data. These
• 12:50were CKD patients,
• 12:52with systemic inflammation.
• 12:54I showed this pretty profound,
• 12:55reduction
• 12:56in, CRP with ziltivekumab. So
• 12:59between eighty five and ninety
• 13:01percent. So really profound,
• 13:03inhibition of inflammation.
• 13:06So we went across and
• 13:07over noticed, there's a few
• 13:08of us, three or four
• 13:09of us talking about what
• 13:10to do with this asset
• 13:11in cardiovascular disease.
• 13:13So being a heart failure
• 13:15enthusiast, I was keen that
• 13:17they tried to address this
• 13:18hypothesis I've just talked about.
• 13:20We've heard about it for
• 13:21twenty years. So why don't
• 13:22we do something?
• 13:23So in a proper collaborative
• 13:25way, and, Eric and myself
• 13:27have been talking about how
• 13:28you work with industry, and
• 13:29it's really important to work
• 13:30with industry alongside them and
• 13:32to talk through plans
• 13:33that influence,
• 13:35properly influence the direction of
• 13:36travel. They were gonna do
• 13:38a trial looking at reducing
• 13:40IL six and heart failure
• 13:42or CRP and heart failure.
• 13:44We said, few of us
• 13:45said, what's the point on
• 13:46that? You're gonna show CRP
• 13:47is reduced. Who cares? It'll
• 13:48take you three years. It'll
• 13:49take you three hundred thousand
• 13:50dollars. Don't do that.
• 13:53So I said, why don't
• 13:54we do this trial? It
• 13:55was just give this drug
• 13:56to people with high CRPs
• 13:57and and HFpEF
• 13:59and see what happens.
• 14:01I thought they were they
• 14:01were gonna laugh and say,
• 14:03you know, go away. Well,
• 14:04we don't wanna take this
• 14:05risk, but luckily, they were
• 14:07wealthy enough at the time
• 14:08to take the risk. So
• 14:10we managed to, convince them
• 14:11to do this trial called
• 14:12the herpes trial, and I'm
• 14:14fortunate to be chairing, the
• 14:15senior committee for this. So
• 14:17five thousand people, very straightforward
• 14:19trial, HFpEF, high CRP,
• 14:21randomized to zoltovecimab
• 14:23or not. So
• 14:24a fascinating trial, primary endpoint,
• 14:27usual heart failure endpoint to
• 14:28turn to first cardiovascular death
• 14:29or heart failure event, and
• 14:31we're gonna complete this trial
• 14:32pretty soon. So I don't
• 14:34know if this will be
• 14:34positive or neutral or negative.
• 14:36We're scrutinizing
• 14:37things like infections and
• 14:39all different types of events
• 14:41in this trial, so we'll
• 14:41do the positives and negatives.
• 14:43I really, really hope this
• 14:45will be positive.
• 14:46There are other trials going
• 14:47on post MI,
• 14:49which are looking at zoltepecamab
• 14:51post MI called ARTEMIS and
• 14:52ZEUS, which is a CKD
• 14:55cardiovascular disease trial as well.
• 14:56So these trials are all
• 14:58finishing in the next two
• 14:59years. So these are coming
• 15:00your way, and I hope
• 15:02really hope they'll be positive,
• 15:03and then we can move
• 15:04on with the anti inflammatory
• 15:06drugs in in cardiovascular
• 15:08disease. There are now new
• 15:10companies that are are springing
• 15:11up, focused only on anti
• 15:13inflammatory drugs with a heavy
• 15:15cardiovascular,
• 15:17angle. So we're discussing other
• 15:19trials and I was talking
• 15:20to, people as well talking
• 15:22about the sarcoid angle, which
• 15:23is a beautiful angle, and
• 15:24there's lots of different niches
• 15:26which could could be identified.
• 15:28This is quite a broad
• 15:29group, but hopefully we can
• 15:30get there quite soon.
• 15:32These are the secondary endpoints.
• 15:34Normally in heart failure trials,
• 15:35we just focus on death
• 15:36and heart failure. But here
• 15:37we are thinking there's a
• 15:38vascular effect. So we've got
• 15:40combined endpoints including
• 15:41MI and stroke as well
• 15:43as heart failure.
• 15:44So moving rapidly onto a
• 15:46totally different area. Eric, mentioned
• 15:49briefly the whole weight loss
• 15:50drugs and heart failure area,
• 15:52which is really interesting.
• 15:54So again about seven years
• 15:56ago, we went to a
• 15:57variety of companies who had
• 15:59weight loss drugs and heart
• 16:00failure, and in my clinic
• 16:02people that were overweight or
• 16:03obese with heart failure seemed
• 16:04to do badly and I
• 16:06was pretty sure these drugs
• 16:07that cause a lot of
• 16:08weight loss would be good
• 16:09for people with heart failure,
• 16:10but we were told that
• 16:12we were crazy because there
• 16:14was a thing called the
• 16:15obesity paradox that people that
• 16:16were heavier did better, people
• 16:18that are lighter did worse,
• 16:20weight loss was bad for
• 16:21you, and these drugs put
• 16:23your heart rate up. So
• 16:24we were gonna kill people.
• 16:25So they said, no, we
• 16:26are not gonna do an
• 16:27outcomes trial because you're gonna
• 16:28kill people. So this was
• 16:30a big deal, and this
• 16:31was across people that had
• 16:33these drugs and we just
• 16:34told there were no way
• 16:35were they were going to
• 16:36do these trials.
• 16:37So we we irritated them
• 16:39and went back to them
• 16:40again and again and there
• 16:41was various different groups actually,
• 16:44around around the world that
• 16:45were approaching, three different prominent
• 16:47groups came together, We created
• 16:48such a noise, we were
• 16:49so irritating, they allowed us
• 16:51to do two of these
• 16:52trials, so STEP FPF and
• 16:54STEP FM FM.
• 16:55There's another trial called Summit,
• 16:56which happened after that.
• 16:58So I'm not gonna talk
• 16:59about this for too long,
• 17:00but the STEP FPF program
• 17:02comprised two different trials. One
• 17:04in people with diabetes and
• 17:05one people without diabetes. But
• 17:07look at the numbers here.
• 17:08These are small trials. So
• 17:09five hundred and six hundred
• 17:10people. These are not mega
• 17:11trials. The trials that we
• 17:12normally do are five thousand,
• 17:14eight thousand, ten thousand. These
• 17:16are small, little, little trials.
• 17:18The endpoints as well, people
• 17:20laughed at these endpoints. So
• 17:21body weight, you've got weight
• 17:22loss drug. You're gonna body
• 17:24weight is your endpoint. Why
• 17:25are why are you doing
• 17:26that? That's crazy. Or quality
• 17:27of life.
• 17:28Importantly, this was semaglutide at
• 17:30the weight loss dose of
• 17:31two point four milligrams against
• 17:32placebo.
• 17:33So a GLP one receptor
• 17:35agonist straightforward GOP not nothing
• 17:37added on. The secondary endpoints
• 17:39are really important. Quite often,
• 17:40these are not important, but
• 17:41for this, they are. So
• 17:43six minute walk hasn't been
• 17:44shifted by lots of heart
• 17:45failure therapies.
• 17:46The hierarchical endpoint was important.
• 17:49So this is a win
• 17:50ratio, death, heart failure events,
• 17:52and quality of life, and
• 17:53CRP.
• 17:54So just one slide in
• 17:56the results. So we we
• 17:57we did, make people feel
• 17:58better, and the magnitude of
• 18:00effect here is really important.
• 18:01So seven point improvement
• 18:03is important. The sg otolipiter
• 18:05trials and other trials are
• 18:06usually one or two points
• 18:08maximum. These people came back
• 18:09to clinic. They loved you.
• 18:11They had a new wardrobe,
• 18:12they could do their shopping,
• 18:13they could walk up a
• 18:14incline,
• 18:15these people were transformed, they
• 18:17loved it. And the weight
• 18:18loss was also seen as
• 18:20well, we all see more
• 18:21weight loss in people without
• 18:22diabetes than with diabetes,
• 18:24But importantly, people could walk
• 18:25further that hadn't happened with
• 18:27previous heart failure therapies.
• 18:28And this clinical hierarchical endpoint
• 18:30of death, hospitalizations, and quality
• 18:32of life was also improved.
• 18:34So we weren't killing people.
• 18:35People now look back at
• 18:36this trial and say, why
• 18:37do you even do that?
• 18:38It's, you know, it's so
• 18:39obvious. But that was that
• 18:40was really important at the
• 18:41time as led on to
• 18:43other trials. The CRP reduction
• 18:45here is interesting too. So
• 18:46some of these effects might
• 18:47be anti inflammatory,
• 18:49thirty five to forty percent
• 18:50reduction of CRP.
• 18:52Now this is
• 18:53for,
• 18:54heart failure trialists. This is
• 18:56almost an embarrassing slide because
• 18:58I'm showing you a slide
• 18:59of outcomes with only thirty
• 19:00eight events in it. So
• 19:02you should be laughing at
• 19:03me and saying, don't show
• 19:04me these data. There are
• 19:05two small numbers.
• 19:07But, actually, there's only eight
• 19:08in the semaglutide arm and
• 19:10thirty in the placebo arm.
• 19:11So on the background of
• 19:12us,
• 19:13we're killing people or causing
• 19:15heart failure. This suggests maybe
• 19:16we're not killing people, and
• 19:18maybe there's a signal of
• 19:19efficacy here. But, certainly, we
• 19:21cannot conclude here that we
• 19:22improve heart failure events on
• 19:23the basis of a small
• 19:24number of trials.
• 19:26The other thing we were
• 19:27petrified about was the n
• 19:28terminal pro bmp and in
• 19:30this trial because people that
• 19:32are are heavier have lower
• 19:34n terminal pro bmp's and
• 19:36lighter have high end pro
• 19:37bmp's.
• 19:38So we thought as you
• 19:39lost weight people's bmp's would
• 19:41go up, people would say
• 19:42you've made people's heart failure
• 19:44worse. So we were delighted
• 19:46that the NT pro bmp
• 19:47went down in this trial
• 19:48and does suggest
• 19:49a possible
• 19:51heart failure mechanistic benefit, but
• 19:53possible heart failure mechanistic benefit.
• 19:55So we were delighted
• 19:56and even better the people
• 19:58that were sicker the higher
• 19:59n terminal proBNPs had greater
• 20:01benefit in terms of improvement
• 20:02of quality of life, So
• 20:03the sicker people, we didn't
• 20:05see bad things happening.
• 20:07And again, sorry to labour
• 20:08this point, but people that
• 20:09lost weight in the placebo
• 20:11arm, their BMPs did go
• 20:12up and people that lost
• 20:13weight in the semaglutide
• 20:15arm, the BMPs went down.
• 20:16So that really was quite
• 20:18encouraging.
• 20:19So alongside
• 20:21our two small trials, there
• 20:22was also trial called SUMMIT,
• 20:24this is with tirzepatide, so
• 20:25this is a GLP one
• 20:26receptor agonist and a GIP
• 20:28agonist as opposed to semaglutide,
• 20:30just a single,
• 20:31single mechanism of action. So
• 20:33similar trial against small again,
• 20:35seven hundred and thirty patients.
• 20:37These were less sick people.
• 20:38So,
• 20:39I was very keen as
• 20:40TEPEPE. We had quite high
• 20:42BMPs. We had BMPs of
• 20:43four hundred and fifty median.
• 20:45Here there was only one
• 20:46hundred and eighty because Barry
• 20:47Borleg and we were having
• 20:49a big argument in Step
• 20:50Pepe, but Milton Packard and
• 20:52Barry ran this trial together.
• 20:53So lowered entomrupo BNP's, lowered
• 20:55event rates,
• 20:57comparing tirzepatide to placebo,
• 20:59And basically, they changed their
• 21:01primary outcome during the trial
• 21:02after seeing our small number
• 21:03of heart failure events. And
• 21:04they they showed similar findings,
• 21:06so reduction in heart failure
• 21:08events, c v death or
• 21:09oral direct intensification
• 21:11against small numbers of events
• 21:13and improvement in quality of
• 21:14life as well and similar
• 21:16secondary endpoints.
• 21:18So,
• 21:19basically, a summit was confirmatory
• 21:21of what our findings were,
• 21:22but against small numbers of
• 21:23events, only thirty eight hospitalization
• 21:25in both of these trials.
• 21:26So inconclusive.
• 21:28Looking further afield in the
• 21:29select trial, you remember select
• 21:31was a, again this is
• 21:32not a heart failure trial,
• 21:33this is seventeen and a
• 21:34half thousand people with overweight,
• 21:36obesity and cardiovascular disease with
• 21:38semaglutide at weight loss dose.
• 21:40And there were there were
• 21:41investigator reported HFpEF people at
• 21:44baseline, so these are not
• 21:45people carefully defined by ECHO
• 21:46and BNP, just investigator reported.
• 21:49And you see the hazard
• 21:50ratio here was point seven
• 21:51five. Again, broad, confident intervals,
• 21:54not too many events, but
• 21:55again signaling possible benefit.
• 21:58So after we've completed these
• 22:00small trials, there's big debate
• 22:01about how much of the
• 22:03the effects are due to
• 22:04weight loss or weight loss
• 22:05independent mechanisms. We can't be
• 22:07sure, obviously, because these people
• 22:08all were obese in the
• 22:09first place, so we can't
• 22:10really pick apart weight loss
• 22:12dependent independent mechanisms.
• 22:14But things like the BNP
• 22:16going down are promising. The
• 22:17BNP went down early. The
• 22:19CRP went down early. I'd
• 22:20suggest there probably are heart
• 22:22failure benefits,
• 22:24over and above, the weight
• 22:25loss benefits, but we don't
• 22:26know that for sure and
• 22:27people need to do trials
• 22:28in non obese populations.
• 22:30We also have seen,
• 22:32good data from the FLOW
• 22:33trial with semaglutide and CKD
• 22:35showing a reduction in heart
• 22:36failure events,
• 22:37and the absence of major
• 22:38weight loss,
• 22:40as well as the the
• 22:41diabetes cardiovascular outcome trials as
• 22:43well showed a small reduction
• 22:44in heart failure events.
• 22:46So to conclude from these
• 22:47small trials, we have shown
• 22:49a reduction in body weight
• 22:50and improvement of quality of
• 22:52life, but not much else.
• 22:53And just to just to
• 22:54emphasize, so deliver, which is
• 22:56a tobacco flosin hep f
• 22:58trial or fine arts, the
• 22:59fine r one had almost
• 23:01two thousand events. Look at
• 23:02the tiny number of events
• 23:03in these trials. So we
• 23:06firmly believe we need proper
• 23:07large outcome trials to quantify
• 23:10the the benefits of these
• 23:11drugs in heart failure, not
• 23:13just the benefits, but it's
• 23:14the safety and efficacy in
• 23:15heart failure.
• 23:17So again, when we finished
• 23:19these trials, we went to
• 23:20a variety of sponsors, and
• 23:22we
• 23:23spoke to some really fantastic
• 23:24people in Amgen,
• 23:26a really cracking team, of,
• 23:29serious people in industry. Again,
• 23:30this is going back to
• 23:31working with industry and finding
• 23:32the right people to work
• 23:33with. So we worked up,
• 23:35Javid Butler and myself are
• 23:36co chairing this, program, the
• 23:38maritime HF,
• 23:39trial. So we've got a
• 23:40proper outcome trial essentially here
• 23:42to see to quantify the
• 23:43safety and efficacy
• 23:45in heart failure with preserved
• 23:46ejection fraction.
• 23:48Nothing very surprising.
• 23:50This drug is actually a
• 23:51GLP one receptor agonist and
• 23:53a GIP antagonist, which is
• 23:54interesting. Perhaps we can talk
• 23:56about that, but otherwise pretty
• 23:58typical.
• 23:59The the number of events
• 24:00is eight hundred and fifty.
• 24:02The finishing timeline is actually
• 24:03twenty twenty eight for the
• 24:04main trial. There's an open
• 24:06label extension going on, after
• 24:08the trial until twenty thirty.
• 24:10The reason for the open
• 24:11label extension is interesting, but
• 24:13we're anxious about people in
• 24:14the placebo arm taking GLP
• 24:16ones open label or not
• 24:18open label just off off
• 24:19trial drug, so we're going
• 24:21to test the blood and
• 24:22urine of people in the
• 24:23trial to detect anybody who's
• 24:24taken these drugs, and people
• 24:26only qualify for their open
• 24:27label extension free two years,
• 24:30and if they stay in
• 24:31the trial
• 24:32and do not have a
• 24:33drug in the placebo arm.
• 24:35So that's,
• 24:36really important that we try
• 24:37and keep people, on the
• 24:38right, strategy.
• 24:40Okay. So another jump onto
• 24:42a completely different area, and
• 24:43this is, hopefully will excite
• 24:45you, this subcutaneous furosemide in
• 24:47heart failure. So about twelve
• 24:49years ago, I met a
• 24:50guy who had developed
• 24:52a a different formulation of
• 24:53furosemide.
• 24:54So in this small vial,
• 24:56this is a three mil
• 24:57vial. There's eighty milligrams of
• 24:59furosemide, so concentrated
• 25:01furosemide in a small vial,
• 25:02which is pH neutral.
• 25:04He's then married it to
• 25:06this modified insulin pump, which
• 25:07you stick in your abdomen.
• 25:08So I'm hoping, and I
• 25:10was when I met this
• 25:11guy, I thought that looks
• 25:12really good. And seeing people
• 25:14lying around in the hospital
• 25:15with a vent with a
• 25:16cannula and
• 25:17getting feeler, getting chest infections,
• 25:20getting staph aureus bacteremia, all
• 25:22these horrible things. I I
• 25:24was thought people could go
• 25:25home with that and and,
• 25:26you know, pee in their
• 25:28own toilets and, you know,
• 25:29carry on their lives to
• 25:30some extent.
• 25:31So we got together with
• 25:33this very small company, and
• 25:35we designed
• 25:36a first in man study,
• 25:37first of all. So that
• 25:38that happened.
• 25:39The bioavailability
• 25:41was actually better than IV
• 25:42furosemide, and people passed just
• 25:44slightly more urine as well.
• 25:46So we we then in
• 25:47Glasgow, we do a lot
• 25:48of our own trials in
• 25:49Glasgow. So we sponsor we
• 25:51run our own trials. So
• 25:52we did this,
• 25:53first in heart failure drug
• 25:55device trial, which takes a
• 25:56lot of effort through regulatory
• 25:58bodies and all the rest
• 25:59of it. So we did
• 25:59this as an academic team.
• 26:02We had we basically got
• 26:03people with heart failure in
• 26:04hospital, put it on them,
• 26:06they peed, they were happy.
• 26:08So we then led that
• 26:10onto a randomized trial. So
• 26:11what we've done is we've
• 26:12identified people who come into
• 26:14hospital with heart failure and
• 26:15congestion, and then we've randomized
• 26:17them to either going home
• 26:19with the drug device pump,
• 26:21seeing them with nursing staff
• 26:22every three days,
• 26:24or staying in hospital on
• 26:25IV fuzumide. So we've we've
• 26:26finished enrollment in this trial.
• 26:28Please don't laugh at the
• 26:29numbers. It's hundred and seventy
• 26:30people, but these are academic,
• 26:31you know, trials we run
• 26:32by ourselves.
• 26:34So we finished,
• 26:35enrollment, and we're we're presenting
• 26:37this next year.
• 26:38Obviously, this is a UK
• 26:39health care environment, so it
• 26:40won't be directly
• 26:42relevant to the US,
• 26:43population or US health care
• 26:45system. But, again, Ambarish Pandey
• 26:47and Java Butler are doing
• 26:48a trial now at the
• 26:49US. Use they're just starting
• 26:51that at the moment. So,
• 26:52hopefully, the days of subcut
• 26:54of IV fuzamide with all
• 26:55big pumps in hospital are
• 26:56gone, and people can go
• 26:58home. Or even before they
• 27:00before they come in, if
• 27:01if people spot them in
• 27:02the community, they can have
• 27:03them put on before they
• 27:04end up in hospital or
• 27:05for palliative care use as
• 27:06well. So I'm enthusiastic about
• 27:08that.
• 27:09So, again, another jump. I
• 27:11hope I'm not jumping around
• 27:12too much, but just another
• 27:13big jump to another area
• 27:14which we're doing an academic
• 27:16trial on,
• 27:17led from Glasgow. This is
• 27:19about the early diagnosis of
• 27:20heart failure. So it's really
• 27:21frustrating
• 27:22when you meet people in
• 27:23hospital.
• 27:24Normally, if you talk to
• 27:25them, they've had symptoms for
• 27:26ages. They've seen their primary
• 27:28care physician. And people only
• 27:29diagnose heart failure faced with
• 27:31lots of ankle swelling, lots
• 27:32of crackles, so towards the
• 27:34end stage of disease. So
• 27:35early diagnosis, I think, is
• 27:37one of the keys to
• 27:37heart failure. And we've kinda
• 27:39got the tools these days.
• 27:40There's been big improvements in
• 27:41point of care, n terminal
• 27:42proBNP,
• 27:44and artificial intelligence echo in
• 27:46terms of both AI to
• 27:48guide acquisition and also the
• 27:50reporting.
• 27:50So this is fascinating. So,
• 27:52basically, we had an idea
• 27:54for a trial,
• 27:55which we're, again, we're running
• 27:56from Glasgow, and we're so
• 27:58we're doing this trial. Again,
• 27:59Erica and myself were talking
• 28:01yesterday about the balance between
• 28:02the industry trials and academic
• 28:04trials. So this is funded
• 28:05by AstraZeneca, but they've got
• 28:06nothing to do with it.
• 28:07So they give us the
• 28:08money, and we run the
• 28:09trial, all aspects of the
• 28:11trial, from the academic team
• 28:13in Glasgow. They do they
• 28:14know nothing about what's happening.
• 28:16They've got no no rule
• 28:17in the mechanics of the
• 28:18trial.
• 28:19So with with the countries
• 28:21we're using, we're trying to
• 28:22develop networks of people that
• 28:24want to work with us
• 28:25in the same kind of
• 28:26way to answer a clinically
• 28:27relevant question.
• 28:28So we've got people in
• 28:29Denmark, and they are fantastic
• 28:31people in Denmark. They've done
• 28:32all the MI trials, the
• 28:33ICD trials, lots of fantastic
• 28:35trials, and Eric and myself
• 28:37have worked with some of
• 28:37the key people there at
• 28:38large COVID over the years,
• 28:39so Lars is involved in
• 28:40this.
• 28:42We're also people in Sweden
• 28:44as well,
• 28:46and and, Canada. We've got
• 28:48Cleveland in America,
• 28:50and Scotland as well.
• 28:52So what we're doing internationally
• 28:54is we are doing this
• 28:55trial where we're randomizing people
• 28:57identified in primary care,
• 28:59to either to pay identify
• 29:01in primary care with two
• 29:02risk factors for heart failure.
• 29:03We then get we then
• 29:05randomize them to either coming
• 29:06up for NT proBNP,
• 29:08and if NT proBNP is
• 29:09above one two five and
• 29:11AI echo or usual care.
• 29:13So the way we're doing
• 29:14this varies internationally.
• 29:16So in Denmark, medical students
• 29:18are doing the NT Pro
• 29:19BNP and the echo. So
• 29:21people have not trained at
• 29:22all before. They do twenty
• 29:23training echoes, and then they
• 29:25do the the screening the
• 29:26the AI echo in terms
• 29:28of acquisition and reporting.
• 29:30In Sweden, it's nurses.
• 29:33In Scotland, we've got experts
• 29:34doing it as well. So
• 29:36we've got different models and
• 29:37different ways of identifying from
• 29:38the registries in Scotland. We've
• 29:40got diabetes registry.
• 29:42In Sweden, a social media
• 29:44campaign. So every country, we
• 29:46we're doing different, but we're
• 29:47harvesting the data into Scotland.
• 29:48So stand alone trials in
• 29:50each country, harvesting the data
• 29:51into,
• 29:52Scotland to look at the
• 29:53overall effects.
• 29:55Primary endpoint is incredibly simple,
• 29:57just how much heart failure
• 29:58you find at six months,
• 29:59and you can see there,
• 30:00treatment of heart failure, secondary
• 30:02endpoint.
• 30:03Interesting exploratory endpoints are death
• 30:05and hospitalization
• 30:06for heart failure, which we're
• 30:07capturing in all these countries
• 30:08from routinely collected data. So,
• 30:11again, data is really important
• 30:12for all of us to
• 30:13use properly. So we're doing
• 30:14more and more trials where
• 30:15we're capturing the endpoints from
• 30:17governmental records.
• 30:19So that's a major challenge.
• 30:21So the Scottish arm of
• 30:22this is finished recruitment, and
• 30:24we're just in the follow-up
• 30:25stage. So we're aiming to
• 30:26present this at the ACC.
• 30:28So this is a diabetes
• 30:30trial in Scotland, so diabetes
• 30:31plus one other risk factor.
• 30:33And, we will,
• 30:35hopefully
• 30:36identify
• 30:36how much heart failure we
• 30:38find. And this is obviously
• 30:39not a blinded trial, and
• 30:41I can tell you we
• 30:41find a a lot of
• 30:42heart failure. So, hopefully, we
• 30:44can blow the world apart.
• 30:45And these diabetes clinics where
• 30:47they look at the eyes
• 30:47and the feet the kidneys
• 30:48and they kinda miss the
• 30:49big pumping thing in the
• 30:50chest, Hopefully, we can, try
• 30:52and get, you know, in
• 30:53the in the diabetes clinics,
• 30:54people focusing on on heart
• 30:56failure and, you know, identifying
• 30:58it.
• 30:59Okay. Another big jump to
• 31:01another area, and,
• 31:03this is where Eric and
• 31:04myself bonded, majorly.
• 31:07And the Stitch and Stitches
• 31:08trial was fascinating from my
• 31:10point of view. So I
• 31:11was a guy in the
• 31:12cath lab, cathing people,
• 31:14looking at terrible convaries, terrible
• 31:16hearts, thinking, wow. If we
• 31:18revascularize
• 31:19these people, we're gonna have
• 31:20massive benefit.
• 31:21So I was sitting innocently
• 31:23in my,
• 31:25small hospital in Glasgow,
• 31:27and,
• 31:28I basically met, Bob Jones,
• 31:30who was a surgeon involved
• 31:31in the trial. And this
• 31:32guy, who was a Duke
• 31:34senior,
• 31:36surgeon, had made the effort
• 31:38to come around the world,
• 31:39talk to people like me,
• 31:40just one to one in
• 31:41a room. I tried to
• 31:42get my colleagues to come.
• 31:43Nobody would even speak to
• 31:44the guy, and I spoke
• 31:45to him. I thought, this
• 31:45guy is amazing. Let's get
• 31:47on board. Then I was,
• 31:49introduced to Eric, who was
• 31:51the powerhouse behind delivering this
• 31:53and really had
• 31:55an incredible experience. We welcomed
• 31:56into this academic research team,
• 32:00and, you know, just the
• 32:02the
• 32:03the experience was so remarkable
• 32:05that around the world, people
• 32:07that just got involved, got
• 32:08stuck in, wherever they were,
• 32:10got brought into this trial,
• 32:12which is answering this a
• 32:14clinical question in an academically
• 32:16led trial. And whenever you
• 32:17see trials, industry trials, I'll
• 32:19show you one later on.
• 32:20We've got I'm I'm basically
• 32:21reading, we've got twelve hundred
• 32:23sites run by industry. These
• 32:25are difficult trials, and this
• 32:27is randomizing to surgery or
• 32:29medical therapy.
• 32:30Imagine how difficult that conversation
• 32:31is with a patient. So
• 32:32we did this trial of
• 32:34really twelve hundred people around
• 32:35the world. And personally, this
• 32:37basically launched VIN to being
• 32:39really involved in research. So
• 32:40I'm gonna thank, the the
• 32:42Stitch team for for that.
• 32:44But anyway, clinically
• 32:45relevant to this is massive.
• 32:47So, these results I'm sure
• 32:48you've seen before, but the
• 32:50surgical arm did worse for
• 32:51the first two years, played
• 32:53the catch up from the
• 32:54ICU
• 32:54sternotomy experience,
• 32:56and gradually caught up over
• 32:57the years. So, two years,
• 32:59crossover curves,
• 33:01five year,
• 33:03not a significant benefit. But
• 33:04at ten years, a meaningful
• 33:06lengthening of life by a
• 33:07year and a half. So
• 33:08people gained a year and
• 33:09a half. We did I
• 33:10looked this morning, there was
• 33:12around fifty one papers from
• 33:13this trial, which is pretty
• 33:15remarkable. Not but not just
• 33:16papers for the sake of
• 33:17it, clinically meaningful papers.
• 33:19And I was allowed to
• 33:21read one of the age
• 33:22papers, and the age paper
• 33:23showed that really the benefit
• 33:25is the people aged less
• 33:26than sixty years of age.
• 33:27So really fascinating. We did
• 33:30diabetes paper as well, which
• 33:31is fascinating, showing no difference
• 33:33in the benefit in diabetes
• 33:34and no diabetes.
• 33:36People miss don't don't know
• 33:37that. You hear in heart
• 33:38team meetings, people thinking that
• 33:39diabetes
• 33:40people benefit more from surgery.
• 33:42That's not true in heart
• 33:43failure. Anyway, this was a
• 33:44really fantastic experience.
• 33:46So,
• 33:49following on from that, being
• 33:50a stent jockey in the
• 33:51cath lab, I thought, do
• 33:52you know what? Surgery
• 33:54is obviously good in the
• 33:55longer term, but we can
• 33:56do better with PCI because
• 33:58people could they don't have
• 33:59to go have a sort
• 34:00of sternotomy, don't have to
• 34:01go to ICU. We just
• 34:02blast these colonies open. We
• 34:04stick in lots of stents.
• 34:05The the angiographic results are
• 34:06phenomenal.
• 34:07We'll we're gonna blow this
• 34:09out in the park. So
• 34:10we got together in the
• 34:11UK, and Devaka Pereira was
• 34:12the first authorized, last author.
• 34:14We basically designed this trial
• 34:16we thought to be a
• 34:16winner for interventional cardiology. So
• 34:18we got bad coronary's,
• 34:20bad hearts, and mandated viable
• 34:22myocardium.
• 34:23So we randomized people. We
• 34:25steaded the hell out of
• 34:26them. We had great results
• 34:27in the cath labs. We
• 34:28were high fiving.
• 34:29And then,
• 34:31Tovac and myself did the
• 34:32database lock thing, which was
• 34:34absolutely,
• 34:35remarkable, and we basically found
• 34:37that we had absolutely no
• 34:38benefit. So So I left
• 34:39the cath lab and, did
• 34:42trials in other areas. So
• 34:43this is,
• 34:45fascinating, but there's lots here,
• 34:48to go.
• 34:49So basically, there's lots of
• 34:50gaps here. So basically,
• 34:52Stitch is now quite an
• 34:53old trial, so the medical
• 34:54therapy is quite historic.
• 34:56The Stitch was CABG against
• 34:57medical therapy with no PCI
• 34:59arm, revived or not CABG
• 35:01eligible.
• 35:02So that was kind of
• 35:03interesting. They were people from
• 35:04heart failure clinics.
• 35:06So the big gap is
• 35:07in people, a sort of
• 35:07broad group of people with
• 35:09low ejection fraction, less than
• 35:10forty percent, including NSTEMIs.
• 35:12So we've kind of built
• 35:14on the experience from Stitch
• 35:15and Revive. We've got the
• 35:16teams together. We've merged the
• 35:18datasets. We're producing papers. That's
• 35:20really rewarding.
• 35:21We've now set up a
• 35:22whole bunch of trials now,
• 35:24which are
• 35:25set up in different countries.
• 35:26This is at the UK
• 35:27trial, CABG against PCI and
• 35:29heart failure called BSIS four.
• 35:31You can so all of
• 35:32our countries have got different
• 35:34trials. We're gonna merge the
• 35:35data,
• 35:36into Gothenburg and Sweden. So
• 35:38these are these are the
• 35:39the different trials that are
• 35:41funded.
• 35:42The Canadian trial is gonna
• 35:43involve Yale.
• 35:44There's,
• 35:45the Swedish trials involving South
• 35:47Africa and Egypt. So we've
• 35:49got a kind of international
• 35:50network.
• 35:51We should end up with
• 35:52a lot of people and
• 35:53good data,
• 35:54to understand the role of,
• 35:56PCI against CABG and modern
• 35:58heart failure.
• 36:00So, HFpEF is the next
• 36:02thing. So we did an
• 36:03observational study with our fellows
• 36:05in Glasgow showing that almost
• 36:06everybody with HFpEF has coronary
• 36:08artery disease to some extent,
• 36:10about ninety percent of people.
• 36:11So we're doing now a
• 36:12sham controlled
• 36:14trial,
• 36:15in HFpEF or PCI
• 36:17with a hierarchical endpoint of
• 36:18death, hospitalization for heart failure,
• 36:19and quality of life. So
• 36:21this is the next frontier
• 36:22in the area.
• 36:24I'm gonna stop talking relatively
• 36:25soon because I think I'm
• 36:26in forty five minutes, so
• 36:27I'm gonna talk relatively soon.
• 36:28So just prevention is the
• 36:29next thing. I think most
• 36:30people,
• 36:31understand that preventing heart failure
• 36:32is better than waiting for
• 36:33it to happen. So there's
• 36:35a massive great, area of
• 36:36interest here.
• 36:38Of course, the different,
• 36:39causes of heart failure will
• 36:41lead to different strategies to
• 36:42prevent heart failure. And this
• 36:44is just to say that
• 36:45there are big movements in
• 36:46these areas now. So,
• 36:48the industry are very keen,
• 36:50to get involved here. So
• 36:52these are big trials. These
• 36:53are almost twelve thousand people
• 36:55now using aldosterone synthase inhibitors.
• 36:58I'm sure you all know
• 36:59these new drugs that,
• 37:00MRAs obviously are underused.
• 37:03MRAs actually cause increase or
• 37:05result in increased aldosterone levels,
• 37:07so to inhibit aldosterone
• 37:09at the synthesis level makes
• 37:10more sense. So, again, we're
• 37:12doing these large trials,
• 37:13which these are the kind
• 37:15of trials that are not
• 37:16academic trials like the ones
• 37:17that we're talking about with,
• 37:19with, you know, PCI, CABG,
• 37:22subcutfruzomide,
• 37:23early detection of heart failure.
• 37:25So I'm gonna talk about
• 37:26AF ablation quickly before I
• 37:27stop. So just, AF ablation,
• 37:29fascinating area in heart failure.
• 37:32So AF ablation heart failure,
• 37:33what's the role? When When
• 37:34I was a newly appointed
• 37:35consultant, this paper came out
• 37:36in the England Journal observational
• 37:38study, massive improvement injection fraction.
• 37:40I thought that's the way
• 37:41to go. So, again, we
• 37:43did a this is an
• 37:44academic trial run by Glasgow.
• 37:45No industry involved. We did
• 37:47a small trial, local trial,
• 37:49forty patients, showed us very
• 37:51small
• 37:51improvement injection fraction. This is
• 37:53ran the first randomized trial
• 37:54ever. We couldn't get anybody
• 37:56to publish it. So Hart
• 37:57wouldn't publish it. Jack wouldn't
• 37:59publish it. So we're publishing
• 38:00Hart actually in the end,
• 38:01so nobody would publish this.
• 38:02For some reason, I couldn't
• 38:03get published.
• 38:04So
• 38:05I'll just very briefly,
• 38:07talk about castle a the
• 38:09castle AF. I'm sure you
• 38:10know this trial. This has
• 38:11been incredibly influential.
• 38:13This is this is AF
• 38:14ablation against no AF ablation
• 38:16and heart failure. I just
• 38:17did to I'll just go
• 38:19quite quickly here just to
• 38:20criticize it. Huge treatment effects.
• 38:22So apparently,
• 38:23a forty seven percent reduction
• 38:24of cause mortality.
• 38:26This is only a three
• 38:27hundred and sixty three patient
• 38:28trial. There was twenty percent
• 38:30crossovers,
• 38:31ten percent lost to follow-up.
• 38:32So in terms of heart
• 38:33failure trials, this is a
• 38:34low low caliber evidence and
• 38:36hasn't really impacted the heart
• 38:38failure community, but it has
• 38:39impacted the EP community.
• 38:41So I'll just go this
• 38:42is last slide I'll I'll
• 38:43use. So basically, we've managed
• 38:44to get an academically funded
• 38:46trial, so myself and a
• 38:47guy called Pierre Lambiase,
• 38:49an EP colleague in London
• 38:50are, running this trial. So
• 38:52we're we're randomizing twelve hundred
• 38:54people to AF ablation or
• 38:55no AF ablation,
• 38:56with heart failure. We're also
• 38:58doing this internationally,
• 39:00so we have colleagues in,
• 39:02Denmark doing almost the same
• 39:03trial and Canada almost the
• 39:05same trial and we're now
• 39:06we're harvesting the events together
• 39:08as well so we can
• 39:09pool data at the end.
• 39:10Again, this is back to
• 39:11working with people we like,
• 39:12we know, we trust using
• 39:14routinely collected data as well.
• 39:15So I think at that
• 39:16point, I'll stop rather than,
• 39:17talk more. But so thank
• 39:18you for your attention.
• 39:27So, Mark, that was a
• 39:28wonderful,
• 39:29you know,
• 39:30whirlwind tour of what's coming
• 39:32up, and I think you
• 39:33can see it's a very
• 39:34exciting field, and and I
• 39:35think there's,
• 39:36you know,
• 39:37thank you for all your
• 39:38leadership in what you're doing
• 39:39in this space and pushing
• 39:40us forward. I I'll maybe
• 39:42I'll start with a a
• 39:43first question and and see
• 39:44if others have, and we
• 39:45have a lot of inflammation
• 39:46biologists in the room, so
• 39:47I'm curious where where that's
• 39:49gonna lead.
• 39:50But,
• 39:52you know, with
• 39:53the semaglutamide
• 39:55and tirzepatide
• 39:56story,
• 39:57you know, particularly in the
• 39:58HFpEF population, I'm just curious,
• 40:00you know,
• 40:02we've had a tradition of
• 40:03doing,
• 40:06trials where we actually start
• 40:07removing therapies and
• 40:09evaluate the impact of that
• 40:10therapy. We did that with
• 40:12Digoxin
• 40:13years back, and maybe it's
• 40:14come back to bite us.
• 40:15We'll see.
• 40:16But,
• 40:17I'm curious
• 40:19if you
• 40:20feel if you could tell
• 40:21us where you think the
• 40:22evidence is currently,
• 40:24to guide day to day
• 40:26practice. And,
• 40:27in patients who have heart
• 40:29failure symptoms with preserved LV
• 40:31function,
• 40:32who have had an advantage
• 40:34or benefit from weight loss,
• 40:36on semaglutetirizobide,
• 40:39do we start
• 40:41deescalating
• 40:42therapies in that population? Do
• 40:43we move SGL two inhibition?
• 40:45Do we move our settings
• 40:46out? I'm curious where you
• 40:47think the data is and
• 40:48what you would suggest, and
• 40:49maybe it's an idea for
• 40:50another trial. Yeah. So so
• 40:52there are absolutely no data,
• 40:54about withdrawal.
• 40:57I am
• 40:58uncertain about the whole area,
• 41:00and the strategies to test
• 41:02are also broad as well
• 41:03because you can carry on
• 41:04the same dose of drug
• 41:05where you can go to
• 41:06smaller doses or less frequent
• 41:08doses. So for me, I
• 41:10think that I'm a big
• 41:11trialist as you know. So
• 41:12I I think that just
• 41:13needs addressed in an ongoing
• 41:14trial. What we do know
• 41:16is the only thing we
• 41:17know about withdrawal is from
• 41:19the the STEP trials where
• 41:21if you stop it within
• 41:22a year, almost everybody's back
• 41:23to baseline again. So they
• 41:25gain weight again. So the
• 41:26trajectory is steep as well.
• 41:27So if you stop the
• 41:28drug, people go back to
• 41:29where they were. So
• 41:31my personal opinion is that
• 41:32people who,
• 41:35are are living with overweight
• 41:36obesity have a different endogenous
• 41:38level of these things, and
• 41:39they just need those extra
• 41:40levels to to, behave in
• 41:42the same in the same
• 41:43way as other people do.
• 41:44So I think maintenance will
• 41:46be necessary. I don't think
• 41:47it's realistic to expect people
• 41:48to to keep the weight
• 41:50off, but that's that's a
• 41:51very personal opinion. It's not
• 41:53based on anything.
• 41:55There's lots of discussion
• 41:56about,
• 41:58about how what to do
• 41:59at the end of these
• 41:59trials.
• 42:00There's also,
• 42:01you know, fierce discussion about
• 42:03many, many other issues as
• 42:05well, you know, attached to
• 42:06the whole the whole area.
• 42:07So I think for people
• 42:09in the room, the the
• 42:10the amount of trials in
• 42:11the area we need done,
• 42:13HFREF,
• 42:14improved ejection fraction,
• 42:17again, where to stop in
• 42:18terms of the trials even
• 42:19when you're on the drug
• 42:19because people lose a lot
• 42:21of weight. So do you
• 42:22carry on until their BMI
• 42:23is twenty or twenty four
• 42:25or twenty two? So we're
• 42:26having active debates about that
• 42:27as well. So this is
• 42:29a area for all of
• 42:30us to study, and within
• 42:32five or ten years, we
• 42:33will know it. But we
• 42:34don't know we know nothing
• 42:35about these things, these drugs.
• 42:40A little bit because he's
• 42:41our cardi Metabolic expert,
• 42:43to kinda give us his
• 42:44perspective on on on that
• 42:46construct of de escalation of
• 42:48drugs when you've met a
• 42:49a certain weight loss goal
• 42:52and have cardiovascular
• 42:54problems.
• 42:57Okay. Yeah. Put your they
• 42:58got big time. Big time,
• 42:59man. Say. Well
• 43:01No. I think
• 43:02the the issue with these
• 43:03drugs is how much is
• 43:05weight loss and how much
• 43:06is is direct anti inflammatory
• 43:08and other metabolic effects. And,
• 43:11you know,
• 43:12it would be of interest,
• 43:13I don't think anybody's gonna
• 43:15do it, to take
• 43:16patients who are
• 43:19mildly overweight, I e not
• 43:21obese,
• 43:22and test at low dose
• 43:23where those drugs might have
• 43:24some beneficial biological effects.
• 43:27I don't know if you
• 43:27wanna comment on that. So
• 43:30my personal opinion is that
• 43:31this area is so hot.
• 43:32People will do trials of
• 43:34non obese heart failure populations,
• 43:36but they will follow these
• 43:38trials because,
• 43:40these trials are it's like
• 43:41an open goal. The goalkeeper
• 43:42is not there. These these
• 43:44are, you know, really simple
• 43:45trials.
• 43:46But, you know, the the
• 43:47the gain here is massive.
• 43:48I think most of us
• 43:49are pretty convinced there are
• 43:50benefits to be had. So
• 43:51I don't even think you
• 43:52need overweight.
• 43:53I think we should be
• 43:54testing in people who just
• 43:55are not overweight or obese.
• 43:57That's the only way to
• 43:58to test it. Obviously, there's
• 44:00mechanistic trials you could do,
• 44:01which would be a start,
• 44:02and then there's outcome trials.
• 44:03Maybe the mechanistic trials will
• 44:05be a reasonable way reasonable
• 44:06place to start. But, again,
• 44:08these young people in the
• 44:09room, they will definitely live
• 44:11through an era where they
• 44:12see the trials done in
• 44:13non obese populations.
• 44:15That's my,
• 44:16my opinion.
• 44:19That's fine. Next, I guess.
• 44:25Good.
• 44:27Congrats for your impacting
• 44:29in all these areas.
• 44:31So,
• 44:32Eric would be disappointed if
• 44:34some of the inflammation
• 44:35biologists didn't ask questions here.
• 44:38But,
• 44:39you
• 44:40you know, inflammation is a
• 44:42term that we use, and
• 44:43it can be
• 44:44five hundred different things, if
• 44:46not if not more.
• 44:48You described
• 44:49CANTOS, so anti IL one,
• 44:52anti l six
• 44:53trials,
• 44:55GOP one receptor and,
• 44:58agonist trials, all of which
• 45:00reduce CRP and improve heart
• 45:02failure outcome.
• 45:03And I'm wondering if there's
• 45:05any
• 45:06knowledge or sense of of
• 45:08mechanistic
• 45:10common drivers
• 45:11that
• 45:13each and every one of
• 45:14these
• 45:15drugs or pathways may be,
• 45:17let's say, downstream of so
• 45:19that we could potentially target
• 45:22something farther upstream
• 45:24and make this much a
• 45:25much more effective earlier specific
• 45:28Yeah. Treatment. Yeah. So
• 45:30I think it's it's it
• 45:31is the time to be
• 45:32an information biologist so that
• 45:34your your your skills will
• 45:35be sought after.
• 45:37And there's there are companies
• 45:38now who have got a
• 45:40whole range of anti inflammatory
• 45:41drugs. I'm sure you know
• 45:42this. So there there are
• 45:44companies with
• 45:45NLRP three inhibitors, is there
• 45:47inflammatory inhibitors
• 45:48and other inhibitors, other inflammasomes
• 45:50and other and lots of
• 45:51cytokines.
• 45:52So
• 45:54they they're all very, very
• 45:55quickly moving towards clinical trials.
• 45:57So I'm slightly concerned that
• 45:59we're going ahead of the
• 46:00knowledge and we're trying to
• 46:01just, you know, find a
• 46:03population that benefits. So,
• 46:06the answer is upstream, yes.
• 46:07And the obvious things are
• 46:09are the NRP three and
• 46:10flammosin inhibitors, and that's that's
• 46:11obviously
• 46:12where people are really going.
• 46:14So I think to be
• 46:15honest with you, if those
• 46:16drugs had been more advanced
• 46:18in development before zoltevecimab,
• 46:20that probably would have been
• 46:22a decent,
• 46:23drug to use.
• 46:24So I think we need
• 46:26to do more. Luckily, there's
• 46:27lots of biobanking going on
• 46:28in these trials. So there's
• 46:29these three trials, Novo Nordisk,
• 46:32our biobanking every everything. So
• 46:34and there's plans to analyze
• 46:35everything. So I'm hoping we'll
• 46:37get knowledge out of these.
• 46:38Even if the trials are
• 46:39neutral, we will have knowledge,
• 46:40and then we can move
• 46:41on. And maybe we identify
• 46:42different populations with different things.
• 46:44But,
• 46:45people with your knowledge obviously
• 46:47should get, you know, should
• 46:48be closely involved. I I
• 46:49gotta say Paul Redcar and
• 46:50Peter Libby are pretty pretty
• 46:52good. So,
• 46:53Paul's Paul's tightly involved. But
• 46:55the post MI environment is
• 46:57totally different. You know, the
• 46:58fresh scar, you know, what's
• 47:00happening with inflammatory cells with
• 47:02fresh scars, completely different than
• 47:03a chronic stable Hepa patient,
• 47:06which was different than CKD
• 47:07patients. So I think we're
• 47:08a bit simplistic at the
• 47:09moment, but I I I
• 47:11I'm encouraged by the biobanking,
• 47:13which which should reschedule a
• 47:15lot a lot of light
• 47:15into what we're doing. Yeah.
• 47:16Thank you.
• 47:22Thank
• 47:25you so much for this
• 47:26incredible talk.
• 47:28Really incredible to see all
• 47:30of the trials that have
• 47:31affected the way that we
• 47:32learn cardiology practice now today
• 47:34as cardiology fellows.
• 47:36My question is about the
• 47:37revived and stitch trials.
• 47:39What, like, I have kind
• 47:40of perceived as, like, the
• 47:42revived stitch paradox of reperfusion
• 47:44in ischemic cardiomyopathy without symptoms
• 47:46of angina
• 47:47or excluding kind of the
• 47:48anginal symptoms. Do you have
• 47:50any insights as to the
• 47:51explanation of that discrepancy?
• 47:53Is it, you know, instant
• 47:54restenosis that's the predominant explanation,
• 47:57or are there more kind
• 47:59of, technical
• 48:01elements regarding how the trials
• 48:02were conducted that could explain
• 48:03that discrepancy?
• 48:05And, also,
• 48:07the LVEF cutoff. So, like,
• 48:09in the thirty five to
• 48:10fifty percent range, those kinds
• 48:11of, like, nonsevere cardiomyopathy.
• 48:15Yeah. So it there's quite
• 48:17a lot to discuss there.
• 48:18So revived
• 48:19my opinion about revived was
• 48:21we took those people at
• 48:22heart failure clinics. So they
• 48:23weren't cath lab people with
• 48:24low ejection fractions. They were
• 48:25heart failure people came into
• 48:27the to the cath lab.
• 48:28We cath them. They had
• 48:29terrible congeries and terrible hearts.
• 48:31I think it's
• 48:33too late essentially to to
• 48:34think that, you know,
• 48:36revascularization
• 48:37of those thick and scarred,
• 48:39horrible hearts, was gonna help.
• 48:41Although they did have mandated
• 48:42viability,
• 48:43but as Eric's drawn us
• 48:45towards what is viability, we
• 48:46do understand viability.
• 48:48The MRI viability
• 48:50data is based on forty
• 48:52one patients and, you know,
• 48:53it's really it's not great,
• 48:54the derivation of validation.
• 48:56Then we put lots of
• 48:57stents in them, so I'm
• 48:58sure that's instead of a
• 48:59stenosis, you know, stent thrombosis
• 49:01probably didn't help either, but
• 49:03whatever. They they I think
• 49:04their disease process is driven
• 49:05by their bad ventricles and
• 49:06those outcomes due to due
• 49:08to the
• 49:09pump dysfunction rather than the
• 49:11coronary perfusion. So that survived
• 49:13Stitch did show benefit, but
• 49:15of course, in Stitch we
• 49:16had CABG, we had upfront,
• 49:19harm, from surgery, but then
• 49:21the the I think ALIMA
• 49:22is still a valuable thing
• 49:24in younger people with heart
• 49:25failure. So there is benefit
• 49:26there. And I'm sure that
• 49:27having a ALIMA perfusing in
• 49:29the front yard protection against
• 49:31future events is probably a
• 49:33good thing. So,
• 49:34you know, I think there's
• 49:35so much to understand about
• 49:37what's driving
• 49:38driving things. The people with
• 49:40higher rejection fractions, I I
• 49:41think is different. And we've
• 49:42intentionally gone up on our
• 49:44new trials to forty percent,
• 49:45so they're not terrible hearts.
• 49:46They're gonna have a bit
• 49:47better. So I think the
• 49:49risk profile or the the
• 49:51the mechanisms will be different
• 49:52than those people with better
• 49:53hearts.
• 49:54So we're kinda hoping to
• 49:55recruit quite a lot of
• 49:56them, and then we can
• 49:57understand what's
• 49:59But there's it's an operation
• 50:00going on. We'll have lots
• 50:01of patients who can
• 50:03do proper analysis of subgroups
• 50:05and and understand them with,
• 50:07with, enough numbers to have
• 50:08meaningful analysis.
• 50:14Thank thank you again.
• 50:16So I have a I
• 50:17have a question on this
• 50:19whole kind of early diagnosis
• 50:21universal screening of kinda heart
• 50:23failure almost.
• 50:25Now that we know
• 50:26essentially that heart failure is
• 50:28actually, like, multiorgan dysfunction and,
• 50:30like, very, like, you know,
• 50:32multipathway dysregulation,
• 50:34and now that we know
• 50:35that there's, in HFpEF, essentially,
• 50:37like, universal adiposity
• 50:39or, like, you know, dysregulation,
• 50:41of, like, adipose tissue.
• 50:43Do you feel like from
• 50:44a early diagnosis perspective, it
• 50:46makes sense to screen those
• 50:48people, people who have a
• 50:50lot of visceral adiposity or
• 50:51fat deposition elsewhere rather than
• 50:53kind of a more universal
• 50:54screening approach?
• 50:55So our approach is not
• 50:57universal as we're we're looking
• 50:58for two risk factors for
• 50:59heart failure before we screen.
• 51:01So I may be quite
• 51:02broad about that. So,
• 51:26We're we're running and Sanjeev
• 51:27Shah is doing his heart
• 51:29share registry as well. We've
• 51:31got lots of different HIPAA
• 51:32registries around the world, all
• 51:33linked up, sharing data, and
• 51:35all the same sort of
• 51:36process that that I'm talking
• 51:37about for trials. We're doing
• 51:38that for registries as well.
• 51:40So I think we need
• 51:40to understand HF, so heart
• 51:42failure globally and the risk
• 51:44factors for heart failure. But,
• 51:45you know, Milton's
• 51:47narratives are fantastic, but they
• 51:49I'm not sure it's a
• 51:50whole story. Obesity is important,
• 51:51but there's lots of other
• 51:52things that cause heart failure.
• 51:54So, again,
• 51:56let's look,
• 51:57globally,
• 51:58and I know you're involved
• 51:59with the global, you know,
• 52:01heart failure registries. I think
• 52:02look globally, look at the
• 52:03risk factors, look at the
• 52:04different people to screen. Maybe
• 52:06in America, yeah. Yes. You
• 52:08you screen people that are
• 52:09obese, but in other countries,
• 52:10there's other things which are
• 52:11the major drivers, hypertension.
• 52:14Cardiology is interesting as well,
• 52:15to be honest. That's the
• 52:17other thing is how do
• 52:17you define heart failure? Because
• 52:19what is HFpEF is a
• 52:20big issue because you can
• 52:21define HFF in tons of
• 52:23different ways. I mean, there's,
• 52:24you know, that's why people
• 52:25hate HFF in general medicine
• 52:27or because we've got the
• 52:28different, different definitions, different scores.
• 52:31So there's a massive debate
• 52:33about what HFF is as
• 52:34well.
• 52:37Two more questions, and then
• 52:38I'll maybe cut it off
• 52:40with a comment or two.
• 52:44That's a really wonderful presentation.
• 52:45Thank you.
• 52:46There's emerging evidence that,
• 52:49many of these new antidiabetic
• 52:51medications have antiplatelet effects.
• 52:53And, certainly, it's known that
• 52:55platelets have can release interleukin
• 52:57one b and actually have
• 52:59all the components
• 53:01of the, NLRP
• 53:02inflammasome.
• 53:03And so I wonder
• 53:05what your thoughts are about
• 53:06that.
• 53:07Yeah. So it's it's it's
• 53:08like hearing Paul Richter talking
• 53:10to me. So we have
• 53:10these great conversations because he
• 53:12sees everything from a blood
• 53:13vessel and a antiplatelet perspective
• 53:15and, you know, a blood
• 53:16vessel wall, and I see
• 53:17everything from a heart failure
• 53:18perspective. But, actually, the crossover
• 53:20is massive. As I said,
• 53:21later on, if you look
• 53:23at hep hep people, they're
• 53:24absolutely peppered with vascular disease,
• 53:26with microvascular disease through all
• 53:28their organs and major vascular
• 53:29disease. So I think these
• 53:30are these are very important.
• 53:33If you look at the
• 53:34the reason why people got
• 53:35excited about GLP ones, that
• 53:37was reduction in MI and
• 53:38stroke and cardiovascular death. So
• 53:40I think your point there
• 53:41is very well taken,
• 53:42but,
• 53:44Paul can't think about heart
• 53:45failure because he's a vascular
• 53:46guy. So I kinda joke
• 53:47with him because he thinks
• 53:48Zeus will be positive and
• 53:49I think Hermes will be
• 53:50positive. For me, Hermes is
• 53:51hepep, it's an enriched vascular
• 53:54problem. So if you're right,
• 53:56then then that's even more,
• 53:58reason for our chart to
• 53:59be positive and who knows
• 54:01about his. So I think
• 54:02you're right. The other issue
• 54:04is that
• 54:05the post MI environment, that
• 54:06could that mechanism could be
• 54:08very important post MI.
• 54:09But, again, I'm not sure
• 54:10how that balances with anti
• 54:12inflammatory effects of the healing
• 54:13of the infarct, which I
• 54:14think is an important,
• 54:16thing to try and think
• 54:17of the balance.
• 54:18Great. Thank you.
• 54:20Maybe, one question from Hattie,
• 54:21and then maybe we'll just,
• 54:23comment and finish that. Great.
• 54:25Hi. Thank you. So I'm
• 54:26a basic scientist. I was
• 54:27curious what kind of molecular
• 54:28data are available to collect
• 54:30throughout these patients longitudinally as
• 54:32they're in this clinical trials,
• 54:34especially at the cellular and
• 54:35tissue level, if any? Yeah.
• 54:37So
• 54:37the answer to that is
• 54:39very, very variable across the
• 54:41trials.
• 54:42So most of the trials
• 54:43we're doing are have to
• 54:45be cheap and simple because
• 54:47we're doing international collaborations and
• 54:49essentially collecting body counts and
• 54:51hospitalizations,
• 54:53because that's all we can
• 54:54do. Because we have people
• 54:56if I work with Boringer,
• 54:57they've got, like, you know,
• 54:58twelve hundred sites. But we
• 55:00work