June 29, 2023 • 42 mins
In episode 14 of the CardiOhio Podcast, we interview a legendary clinician, teacher and trialist in American Cardiology, Dr. Steven Nissen from the Cleveland Clinic.
We review his contributions to contemporary trials and lipids and diabetes, as well as his analytic approach to reviewing clinical studies. We then discuss his most recent contribution to the field of lipid therapy, the CLEAR outcomes study published earlier this year.
For additional information on the discussed studies:
Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes
Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients (CLEAR outcomes study)
Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients
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Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
(00:05):
Welcome to the Cardio OhioPodcast, a production of the
Ohio Chapter of the AmericanCollege of Cardiology.
This is Can Greyal in Columbus,Ohio.
This is Ben Allen CherryCardiovascular Imaging fellow
from Cleveland, Ohio.
More information on the podcast,including past episodes, is
available@ohioacc.org.
(00:27):
And now for today's,
Ben (00:31):
All right.
Welcome back to the Cardio Ohiopodcast.
I'm here along with my co-hostKenny Graywall.
We have a very special guesttoday, Dr.
Steve Nissen, who is chiefAcademic Officer at the CDE and
Arnold Miller Family Heart andVascular Thoracic Institute at
Cleveland Clinic.
(00:51):
But I would be remiss to try tostart to name all of the hats he
has worn in the past.
More importantly, one thing hedid with me is he was part of
the recruitment when I went toCleveland Clinic as a fellow.
And I have rounded with Dr.
Nissen in the I C U severaltimes and, and learned a lot
from Dr.
Nissen.
So I wanna introduce Dr.
Steven (01:10):
Nissen.
Well, thank you very much forthat nice introduction.
Ben (01:15):
so, Dr.
Nisson, we wanted to start withfirst, just to let the audience
kind of hear a little more aboutyour story.
We, we asked for like a littleshort biography of our of our
guests and, and kind of just ifyou just take us through an, a
whirlwind tour of, of sort ofthe places you've been since
medical school the hats you'veworn, especially at the
Cleveland Clinic and what you'recurrently doing now.
Steven (01:37):
Okay, so very quickly I went to University of Michigan
Medical School and I then wentto the University of California
Davis for internal Medicineresidency.
And it turns out there I met aninteresting character, a guy by
the name of Anthony Daria.
Tony Daria, who many of youknow, went on to become editor
(01:58):
of the Journal of the AmericanCollege of Cardiology.
But You know, he recognized thatI had an interest in academic
cardiology and so he offered totake me with him when he took
the job as chief of cardiologyat University of Kentucky, and I
went to University of Kentuckyand I did my fellowship there
(02:19):
very quickly.
I was a two year, it wasnominally a two year fellowship,
but frankly it was more like aone year fellowship.
And then I was made the directorof the coronary intensive care
unit, which I.
Loved and did that for a numberof years.
Did some wild and crazy thingsin Kentucky.
Started a helicopter service andused to fly out almost every
(02:41):
night and pick up acute mi, give'em thrombolytics in the, in the
field, in rural Kentucky, andfly'em back to Lexington for
their, their cath, which wasacquired at 90 minutes In those
days, per protocol.
I then got recruited to theCleveland Clinic by the then
chairman Eric Topel as vicechair, and came to the clinic in
(03:05):
the early 1990s, 92, 93.
And while I had been atKentucky, I had developed
intravascular ultrasound, haddone some of the initial work
with it and brought thetechnology to Cleveland and
began to refine it.
Developed a core imaginglaboratory to make measurements.
(03:28):
And while everybody else in thefield thought that intravascular
ultrasound ivus would be used toguide interventions, I thought
it was ideally suited to measureatherosclerosis.
And so I convinced a companythat had this new drug called
Lipitor and that we could showwhether or not.
(03:54):
Attaining a lower cholesterollevel could reduce the
progression of coronary disease.
And so in about 1997, wedesigned the reversal trial.
We finished it and published itin 2003.
It was got a huge amount ofattention because it showed that
(04:17):
lower levels of L D L wereassociated with less.
Disease progression.
It actually ended up on thefront page of the New York
Times, and I then went on with ateam that I had developed here
at the Cleveland Clinic to do an11 more intravascular ultrasound
trials over the next decade orso.
(04:40):
And that for me was an entryinto the larger world of large
randomized clinical outcometrials.
And so it was just one step at atime.
Pull yourself up by yourbootstraps, do the work, you
know, publish it and standbehind it.
And hopefully if you do that,good things will come your way.
Ben (05:05):
That's a that's an awesome recap, Dr.
Nissen.
And I think we're gonna have aseparate podcast for the
helicopter stories
Steven (05:10):
for sure.
Oh my God.
I can tell you war stories thatyou wouldn't even believe.
Kanny (05:17):
So Steve I know you've been also a, as you progressed
from the IVUS trials into someof the other randomized trials
and lipids and other topics, youkinda led.
This this kind of change in howwe approach trials in terms of
safety events with yourexperience with Glitazone.
Yeah.
And we were just curious likehow you got interested in that
specific aspect of clinicaltrials and which has now kind of
(05:40):
become a standard in terms oflooking at, safety
Steven (05:42):
outcomes.
Well, it's actually interestingbecause, you know, you have to
be prepared.
For this sort of finding.
You know, I don't, I didn't golooking for any of this, but in
the year 2001, I got asked bythe F D A to serve on the
Cardiorenal advisory panel, andthe first panel I attended was a
(06:04):
review of a gastrointestinalclaims for a drug known as
Vioxx.
And I looked at the data, youget thousands of patients of
data from the F D A, and I sawthat in every study.
There seemed to be morecardiovascular events in the
(06:25):
people that got RO coxibcompared with other drugs.
And so we collected all of thedata that we could and.
We published a manuscript inJAMA that raised questions about
the safety of, of Roha.
Coxib, otherwise known as Vioxx.
(06:46):
Took a terrible beating.
It was really awful.
Actually the study was led byDeb Mukerjee, who was a
interventional fellow at thetime and now chief of cardiology
at an institution in, in Texas.
And, You know, we got beat up bythe pharmaceutical industry, but
we stu stuck to our guns, andfour years later, the drug was
(07:09):
withdrawn for unequivocal harm.
Then in 2007, I had concerns.
About the diabetes drugglitazone known by the brand
name of Avania.
I had noticed that in clinicaltrials, again, published trials
(07:29):
were relatively limited, thatthe cardiovascular events seemed
to be trending in the wrongdirection and the drug was being
marketed for cardiovascularbenefits, and it didn't make any
sense to me.
So I went looking for more data.
And there was almost nothing,and then I hit a gold mine.
(07:51):
It turns out that the formerattorney General of New York
State Elliot Spitzer, who laterfell from Grace, but Elliot
Spitzer sued the maker of RosaGlitazone GlaxoSmithKline
because the company had hiddendata on hazards.
(08:14):
From their, one of theirantidepressant drugs in teens
and children, teens, youngadults, where there was
increased suicide andsuicidality.
The settlement was for$1, butwith the requirement that the
company post all of the resultsof their clinical trials on a
(08:35):
website.
The website was fairly wellhidden, but I found it.
And I downloaded all of the dataon Rosa Glitazone.
There were 42 clinical trials,35 of which were unpublished,
and my lead statistician, KathyWolski, and I huddled in my
(08:59):
office for a couple of days,wrote a New England Journal of
Medicine manuscript.
Which was a meta-analysis of allthe available data that we had
access to because of thatprevious lawsuit.
Please keep in mind that upuntil this point in time, a
company could do a clinicaltrial.
They didn't like the results.
(09:19):
Nobody ever got to see it callednegative publication bias, and,
and a lot of academics wentalong with that.
Well, what we saw was a 30 to40% increase in.
Myocardial infarction and asimilar increase in
cardiovascular death withglitazone compared with other
(09:41):
drugs.
When that thing hit the, hit thestreets, you know, the New
England Journal of Medicinereviewed it and published it in
21 days, and when it came out,headline news, you know, it was
just incredibly intense.
But the result, Was that at an fd A advisory board meeting in
(10:04):
2008, I proposed that they nolonger approved diabetes drugs
simply because they lower abiomarker blood sugar, that they
had to do cardiovascular outcometrials as a condition of
obtaining approval.
And we worked out a, a system,you know, I proposed it.
(10:25):
The panel agreed the f d A panelagreed and it became a.
The rule and in the years sincethen, all of the trials, you
know, with the SGLT twoinhibitors, the GLP one
agonists, all of the data thatcame out was a result of Seeing
a signal with Rosa Glitazoneacting on the information, being
(10:50):
decisive about writing up themanuscript and publishing it and
standing behind the findings.
And you know, so there were twopretty large, very large, I
mean, headline news, drug safetyissues.
You know, I got accused by somepeople who, for various reasons,
wanted to believe it, that I wassomehow.
(11:11):
An anti-drug industry, which ofcourse is not the case.
We need a great drug industry todevelop new therapies for
patients, but we have to beprepared to tell people what
works, what doesn't work, andwhat's harmful, and to provide
equal weight.
To the findings, regardless ofwhich direction they
Ben (11:34):
go.
And, and Dr.
Nissen, I'll just jump in therebecause I remember hearing the
story as a first year fellowwhen we were rounding in the
unit, and I, I couldn't believeit.
And I wanted to highlight forour listeners that.
You know, indirectly youprobably had a lot of
pharmaceutical mafia people comeafter you, but at the same time,
the this, this sort of action iskind of why we have SGLT two s
(11:57):
and GLP one s because of thatpush for having cardiovascular
outcomes.
So, I mean, you're saying thestory, but I think it's even
bigger than, than this becausethis has shaped some of our
newest drugs that we use in allof these patients.
Steven (12:11):
No one would be able to use these drugs if we hadn't
required the trials because youknow, the pharmacy benefit
managers would say, well, whyshould we pay for a drug when
all it does is lower bloodsugar, the same way of
sulfonylurea or any other druglowers blood sugar.
So it turned out it actuallyhelped the industry, but it
helped patients.
That's what really counts.
(12:32):
And you know, I proudly stoodbehind the data.
It was a very difficult timebecause you know, I can tell you
that if you do take on amulti-billion dollar industry,
they're gonna come after you andyou better have thick skin.
And you better be willing tostand your ground.
But I'm pleased with how it allworked out.
(12:55):
And I do think you're right.
There have a number of peoplehave written about what
happened, and in fact, there was172 page report from the US
Senate after they had held abunch of hearings that goes into
all of the gory details, one ofwhich was unbelievable that when
we submitted the manuscriptwithin 24 hours, one of the
(13:18):
reviewers.
Who had a financial relationshipwith GlaxoSmith Klein gave him a
copy of the manuscript while itwas in review, which is wow
considered highly unethical.
And as a result the company knewit was coming.
And they plotted their strategyon how to character assassinate
(13:42):
The two authors myself and, andMs.
Wolski, and, you know, this allcame out in the Senate report
that the, the, the senatorsdiscovered with subpoenas the
actual facts that had gone fromthe, from the reviewer to the
company.
That had given them a copywithin hours of its submission
(14:05):
of the manuscript I'd submittedto the New England Journal.
Kanny (14:10):
That is a, that's a tremendous story.
We, we are familiar with it, butyeah.
But it's great to hear, it'sgreat to hear her firsthand
accounting of it though.
That's tremendous.
So, so Steve, before we spendthe last 10 or 15 minutes
talking about some of the newer.
Trials.
Yeah.
I did want to ask you, you'vespent, you have so much
experience conducting trialsthat have been so seminal, and
(14:33):
of course you review trials aswell for some of our young,
early practi, early careerpractitioners, our fellows in
training our nursepractitioners.
as you know, the, the medicalliterature has just exploded and
specifically the cardiovascularliterature.
So when you, when you approach atrial as a reader, as a
clinician in your clinician hat,And you're trying to determine,
(14:53):
the relevance and how it mayapply to your patients.
Are there a few things you focuson to help kind of, clear the
wheat from the shaft and figureout which, which studies really
are gonna have impact and, and,and contain actionable
information?
How do you approach, you know,well, that's
Steven (15:10):
a great question.
You, you certainly have to divedeep and I find that some of the
best information.
Is actually in the supplementthat almost nobody else reads,
and I'll give you an example ofthat.
You know, the Reduce Itmanuscript came out with a Casa
(15:31):
Pyl, otherwise known as vascepa,and it just seemed too good to
be true.
And so I'm looking at thesupplement and and buried on the
last page of the supplement ornearly the last page, I find a
single line that shows whathappened to high sensitivity C
(15:52):
reactive protein in the twotreatment arms.
And it turns out that in thecontrol arm, which was a mineral
oil placebo, there was a 30 pluspercent increase.
C-reactive protein unheard of.
And what that led to was aseries of investigations, and I
(16:15):
think there are a lot of peoplewho now agree with me that
basically it's a false positivestudy that instead of using a
neutral placebo, the trial useda placebo that was toxic.
And so the apparent benefits ofACO ethyl were actually due to
the toxicity of the control ofthe placebo and not to the
(16:37):
benefits.
If I hadn't looked deeply intothat supplement, And everybody
else missed it.
Nobody.
Nobody really saw it.
And then later on, Paul Rickerdid an analysis of blood samples
from the trial.
And every inflammatory markeryou can imagine went.
(16:58):
Incredibly bonkers up with themineral oil treatment group.
And so it's a classic example ofa drug that got a, got a label
from the F D A.
It's widely used.
It is not, it does not producefavorable effects.
It's a false positive study.
Yeah,
Ben (17:19):
and I think Dr.
Nissen, that that point ofdiving into the.
Like the details, thesupplemental indices, it's, I
guess the challenge is there'sso many of these clinical trials
that come out and in general,cardiology, you are spanning
prevention, imaging, when tointervene on patients.
How do you, is there a guide youuse, like do you follow certain
(17:40):
journals specifically?
How, what would be your words ofadvice for, for the general
practitioner to make surethey're staying up
Steven (17:46):
to date?
Well, I think first of all, thetier one journals, which are,
you know, jama, new EnglandJournal and the Lancet a lot of
the most weighty researchappear, not all of it, but a lot
of very most important researchappears in those three journals.
And I try to look at them and Ithink there is time for most
cardiovascular practitioners to,to read.
(18:09):
The cardiovascular studies thatare published in those top three
journals, I mean, that's justnot a big lift.
And, you know, look, I work veryhard, you know, I'm one of the
oldest people in our department,but I'm the first one there in
the morning.
I get there at four 30 or fivein the morning every day, off
and on weekends.
(18:31):
I spend the time that I have asproductively as I can, and I do
read the literature carefully soI can stay informed, and it
helps you pose the questions.
That you wanna ask?
You know it's kind ofinteresting because there are
always people that are gonnapush back.
I was just remembering againabout the whole glitazone
(18:55):
controversy.
And when I propose requiringoutcome trials for diabetes
drugs, many people in thediabetes community looked me in
the eye and they said, if you dothis nien, we will never have
another diabetes drug.
Because no company's gonna makethe investment in doing the
outcome trials.
(19:15):
Well, you can see what'shappened since then up just a
proliferation of very, very goodtrials.
Ben (19:23):
Yeah, I definitely agree that that was a courageous move.
And, and kind of before we jumpinto now, the, the current lipid
trials, including clear Yeah, I,I did have a question.
Sometimes we have patientslisten and.
I think it's, it's sometimes aan art to explain to them the
importance of enrolling inclinical trials with the chance
(19:44):
that they get a placebo.
Obviously patients want to betreated.
How, how have you kind ofnavigated that as somebody who's
run several clinical trials?
Yeah, yeah.
Even for example, in the mavacampton trials Yeah.
That you've been involved in.
How do you, how do you kind ofapproach patients in that way?
Steven (20:02):
Well, first of all, patients who volunteer for
clinical trials, it is a nobleendeavor and they do so for very
good reasons.
They do so they will say to us,we know this may not help me,
but if it helps somebody else, Ithink it's worth it.
The other thing that is reallyamazing, there have been
multiple studies published thatpeople that are in the placebo
(20:25):
harm.
Of randomized trials do much,much better than the general
population.
Why is that?
It's because they get very goodmedical care.
They get managed to, you know,with state-of-the-art control of
their risk factors.
They're seeing peoplefrequently, you know, the nurse
coordinator and or the, theprincipal investigator at the
(20:48):
local site.
And so they do better.
And so being, just being in aclinical trial gives you an
advantage over people who arenot in a clinical trial.
And that's the truth.
There's lots of studies thatshow that.
Ben (21:04):
Yeah.
And I can imagine once, oncepatients wrap their head around
that, but also if they have thecourage to continue to, to be
somewhat altruistic, it reallyshapes the field because as much
as the, the clinical trial isrunning the trial, it's the
patients who are involved whopush it forward as well.
You bet.
So, Dr.
Ni, can you just tell us becauseyou noted this, Difference in
(21:28):
the omega-3 trials.
Can you just tell us how fromthe Cleveland Clinic group,
there was a, a, not a rivaltrial, but a, it was sort of
proof of concept trial that wasconducted as well?
Yeah.
How did you kind of
Steven (21:41):
start that?
Well that was started actuallyour trial was with a different
product.
Very similar in many ways, to aCasa Pyl or vascepa.
It was just a little differentformulation and we ran the
trial.
It was, it was actually largerthan reduce it and it showed no
(22:02):
benefit.
There was just nothing and.
We said to ourselves, I, youknow, this was, this was
finished just a few months afterreduce it.
We said, how can one fish oilthat does low risk triglycerides
a little bit, does a few otherthings, show a 25% reduction in
(22:24):
morbidity, mortality, andanother product that is almost
the same chemically show zerobenefit.
Something had to be wrong there.
And the, the, of course, the, I,I had a very good idea what it
was.
And it was the, the problem withthe placebo we used and we knew,
(22:48):
by the way, that mineral oil wasprobably toxic when we designed
the strength trial.
We did was, again, similar insize, you know, 12,000 patients,
I mean bigger in size, 12,000patients.
We chose corn oil as the placebobecause we thought corn oil was
about as neutral as you can get.
(23:08):
We thought olive oil wasbeneficial.
We knew that there were issuesaround mineral oil, so we chose
something deliberately.
That was neutral and there wasno difference between corn oil
and the same four gram dose thatwas used and reduce it with just
a little bit different product.
(23:30):
And so at the end of the day, itjust didn't seem possible that
these two trials could havecompletely opposite results.
Something else had to explainthe differences.
Kanny (23:44):
Yeah.
Thanks Steve.
That that makes sense to set thestage for our last 15 or 20
minute discussion about, youknow, clear and.
Other agents.
I'm, I'm really fascinated by,you know, the concept of statin
intolerance.
I was reviewing some of yourprevious articles about that in
the last several years, and I, Ithink you have a very
(24:05):
interesting definition of it.
And one thing you raised in oneof your, your editorials a few
years back was a concept thatperhaps with statin trials, you
know, the fact that patientshave to be recruited into these
studies, that somehow we'reselecting a group of patients
who are less prone.
To the side effects because, youknow, just like you, I'm a
(24:25):
clinic clinician who's in clinicalmost every day taking care of
patients.
And you know, the concept ofstatin intolerance comes up
almost daily, multiple timeswith our patients.
And of course, when you look atthe literature of, of the
incidents, there's such adichotomy between what we see in
the real world.
And it looked like in some ofyour editorials, you addressed
that.
So I was wondering if you couldjust review how, how you put
(24:48):
that in perspective with some ofyour
Steven (24:50):
patients.
Well, first of all, it is a verycontroversial topic.
You know, there is a group inEurope, in, in the UK that
thinks it doesn't exist.
There are other people thatBuild their entire careers on
the treatment of patients with,with statin intolerance.
You know, my, I have a verypragmatic view of this.
(25:12):
There's two things I reallythink people should know.
One is that most of the clinicaltrials that have been conducted
have a run-in period where youget the drug.
And, you know, if you have aninability to tolerate the drug,
then you're not randomized.
So you have this, this run-in,in advance of actually
(25:36):
conducting the trial.
And so you remove from the studyall the people that are statin
intolerant and the other QuestOther issue is really a very
practical one.
If a patient comes in yourclinic Kenny and says, You know,
I have tried the statins, I'vetried multiple statins.
(25:58):
I can't tolerate the statins andI won't take a statin.
And they have a very high L D Lin their, you know, they've had
a previous event.
What are you gonna do?
You, you can't force a patient,take a drug they don't wanna
take.
And so we have to have practicalalternatives, even if you think
that it's in their head fromthat.
(26:19):
For them it's real.
Kanny (26:22):
Absolutely.
Well, thanks to you and othertrialists.
Fortunately we we're increasingour armamentarium now.
Yeah.
So that so that we do have manymore options.
Ben (26:34):
we're gonna focus on the newest on his newest trial, the
clear trial.
I'm gonna just give a briefsummary so that Dr.
Nissen doesn't have to startfrom, from ground zero here.
The clear trial published in NewEngland Journal was randomized
about 13,000 patients.
Who are at high risk foratherosclerotic cardiovascular
disease and who are unable totake more than a low dose statin
(26:56):
to either the placebo arm or beoacid.
And that's the drug that isbeing tested.
And so they randomized 13,000patients.
And their primary outcome was a,a composite, the standard, major
adverse cardiovascular event,composite of death from CV
causes non-fatal mi, non-fatalstroke and need for coronary
(27:16):
revascularization, and theyfound a a, a significant
reduction.
In Mace.
And, and kind of the, the mainthings that we thought that this
was so applicable clinically wasbecause it, it adds to the
armamentarium for our primaryprevention patients who are at
high risk and don't have optionsbecause of intolerance.
And so from there, just withthat background, Dr.
(27:39):
Nissen I kind of just wanted toask you from the, from the
get-go, what did you foreseewhen you were initially starting
the design of the trial?
Well,
Steven (27:47):
we knew that beo acid is a pro-drug.
It's not active in peripheraltissues.
It gets taken up by the liverwhere it gets converted to its
active form.
And so if it's not active inperipheral tissues, it can't
cause the kno myalgias that manypatients complain about when
they take statins.
(28:08):
And we had pretty good evidencefrom smaller trials that it
didn't seem to produce the kindof musculoskeletal problems and
statins.
Produce.
So it made sense then to studythis drug in statin intolerant
patients.
Now, just wanna make sure youunderstand that about 80% of the
patients were on no statin.
They couldn't tolerate any.
(28:30):
And about you know, 20% or so,were on less than the lowest
approved dose of a statin, likeon 10 milligrams of atorvastatin
twice a week.
That sort of thing.
So these are really people thatare statin intolerant and we
made'em sign a statement thatthey would not take a statin
(28:51):
even though they knew statinscould reduce their risk of heart
attack, stroke, or death.
So we did this in an ethicalway.
I thought it was very importantto do that.
And we were able to find at1,250 sites in.
You know, something like 32countries the patients were
(29:12):
enrolled and, you know, we'vewent on for a number of years.
We followed them for about 41months.
And of course, there's nothingin the world quite like
unblinding, a trial you'veworked on for many years and
finding out whether it worked orit didn't work.
Kanny (29:33):
And I, I know that the trial did include almost 50%
women, which is nice to see aswell.
Yeah.
So I was curious though, you dohave kind of a mix of primary
and secondary preventionpatients in the study.
Have you analyzed anydifferential effect in, in those
two groups, those with known c ad and those with, with risk
(29:53):
factors
Steven (29:54):
only?
I thought you'd never ask.
So you have to come to the a d Ameeting.
It's on the program where we aregoing to present detailed
results in the 30% of patients,4,200 patients.
They were primary prevention.
They had high risk factors, butthey'd never had an event.
(30:15):
And if you looked reallycarefully at the supplement, you
will notice that there appearedto be a more favorable effect in
the patients that were in theprimary prevention strata than
those that were in the secondaryprevention.
We're gonna tell you a lot moreabout that.
I'm gonna present it at ada.
(30:36):
And it will be simultaneouslypublished in a major journal.
Ben (30:43):
And I think that's, that's good.
That's the hook right there, Dr.
Nissen.
And also another plug for youfor us to take a look at the,
the depths of these articles,including the supplementary
indices.
Yeah.
When you, when you talk aboutbedo acid, a lot of, a lot of
what people say about statins isthis pluripotent effect
including on anti-inflammation.
(31:04):
And c r p has been used as a, asa marker for this.
Can you just help us as, as faras statins, we kind of
understand some of that.
But as far as beo acid, what'sits relationship to inflammation
that you found in the trial?
Steven (31:15):
Well, keep in mind that beo acid works in the same
pathway as statins, butupstream, and it has quite
intense anti-inflammatoryeffects.
We got about the same amount ofreduction in high sensitivity C
R P.
As we got reduction in L D Lcholesterol, so it has two
(31:36):
potential ways to benefitpatients, both as an
anti-inflammatory.
And we now know thatanti-inflammatory drugs like
Colchicine or Kinumab do havecardiovascular benefits.
And of course, we've known for along time that L D R reduction
has benefits.
Baic acid does both.
What we didn't study.
(31:57):
And I wish we could have, but wecouldn't for a lot of regulatory
reasons, is the drug isavailable, Beto acid, both as
monotherapy and in combinationwith ezetimibe.
The combination with Ezetimibeproduces a 35 to 40% L D L
reduction.
It's about the same as 40milligrams of simvastatin, and
(32:19):
so we can get a pretty robust LD L reduction with that
combination without having togive a statin to those patients
that simply won't or can't takea statin.
Ben (32:34):
Yeah.
So I think that that's awesomethat that offers another option.
Yeah.
Now to, to speak to this pointthough what has been brought up
is something, something aboutcholelithiasis, something about
gout.
Yeah.
As far as the, the true sideeffects, because we know what
statins cause.
How would you frame that fromwhat you've seen in the, in the
patient outcomes and, and maybejust how you would translate
(32:55):
that clinically.
Do we use it in patients withgout already or use it with
caution, et cetera?
Yeah,
Steven (33:00):
I would be very careful and probably I would not use it
unless I really felt I had noother option in patients with a
strong history of gout.
Unless, of course they had beenon a uric acid lowering agent
for some time and had very good,you know, low uric acid levels.
Those people I would be okaywith.
(33:21):
But, you know, I would worryabout triggering gout.
Now look, if you, if you wannatrade off gout, Versus a heart
attack, I'd kind of take a goutattack any day of the week.
Having said that, you know, wedon't want to be cavalier about
these things.
We had not previously seen csis,but there was an excess, about
1% excess of colonese.
(33:45):
In the Baic acid group, youknow, again, it was generally
not something that led tosurgery or sepsis or anything
like that, but it was an excess,and people need to be aware of
that.
Look, let's be very clear, thereis no such thing as a free
lunch.
Every drug we give patients haspros and cons.
(34:08):
It's important, I think, forclinicians to know the upside.
To know the downside and to makean educated decision with the
patient at the table, so-calledshared decision making.
Lay out the risks, lay out thebenefits, make a decision
together on what direction togo.
Kanny (34:29):
Steve I was also there in the audience at a ACC C when you
presented this to muchexcitement.
I, I know there were, there wasone question asked at that time
about the fact that, you know,you had a.
Combined out outcome, not amortality benefit directly.
Yeah.
And yeah, and you know, I'mwondering do you think that's
relevant or do you think thefact that most likely this is
(34:51):
gonna be used in combinationwith Ezetimibe and further LDL
lowering, and of courseEzetimibe has pretty good
evidence base behind it now, doyou think that makes the
mortality issue a little lessrelevant?
Steven (35:01):
Yeah.
Okay.
It's not irrelevant.
It's highly relevant, but here'sthe issue.
Both large PCSK nine inhibitortrials, one of which was 27,000
patients had absolutely nobenefit on mortality with a 50%
L D R reduction.
Almost all the modern trials insecondary prevention patients
(35:25):
have not shown a reduction inmortality.
We didn't see it for Alloc, forEvolocumab.
You know, I could go on and onand on about the trials that did
not show a death benefit.
Why is that?
It's because of everyonelistening to this podcast.
We've become very good attreating people with acute mis.
(35:49):
People don't die of acute MIvery often anymore.
They may die.
7, 8, 10 years down the road.
Or they may ultimately later ondevelop heart failure, but they
don't die in the short run.
And so I don't think we're gonnasee lipid lowering therapy even
with these very powerful L D Llowering drugs.
(36:12):
Reduce mortality.
We didn't see with baic acid, wedidn't see it with PCSK nine
inhibitors.
It's just too much of a reach inthe contemporary era.
Kanny (36:24):
Yeah, and I think that does make complete sense, so
thanks for clarifying.
So as we kind of put this studywith Bedo acid in perspective
with so many other, you know,existing or agents that are on
the way, I'm just curious tofinish up in the last five
minutes or so how you approach,you know, all of the statin
(36:46):
alternatives now in your mind.
Obviously we know that forprimary, excuse me, for
secondary prevention patients,we're always gonna start with a
high dose statin.
And we know, we know we havevery good data about target
LDLs.
But how would you rank this drugwith say, PCSK nine inhibitors,
which you just mentioned, aswell as Zein and some of the
(37:07):
others as you approach a patientwho say statin intolerant.
And then as a follow up, apatient who doesn't get to go.
On the maximum statin dose theycan tolerate.
Steven (37:18):
Well, Kenny, you said something interesting, which of
course, which I agree with,which is that we have good idea
of what target staff for L D L.
Unfortunately, we haven't beenable to convince our guideline
writers that that's the, thatthat's the case.
But having said all of that I dobelieve that lower is better.
And the higher the risk thepatient, the lower you wanna go.
(37:41):
Statins are the first line drug.
They're the second line drug,and they're the third line drug.
And we try, try and try again.
If we get'em on, get patients ona statin and their l d L is
still above where we want it.
The natural thing to do is toadd ezetimibe because it's
generic, it's inexpensive, it'svery well tolerated, very safe.
(38:05):
There will be people that willnot get there.
With adding ezetimibe, and theywill need a PCSK nine inhibitor.
And that includes now lyran,which is a, you know, very
attractive drug because it's solong acting that you only have
to give it twice a year ifpeople cannot tolerate
(38:27):
evidence-based.
Doses of statins, well then wehave alternatives like beo acid
or beo acid with ezetimibe, andif they need a lot of L D L
reduction, then even beo acidwith ezetimibe may not be
enough, and we may need to go toa PCSK nine inhibitor.
Here's what's really fantastic.
(38:50):
We have a lot of tools in thetool chest, and we can pick them
based upon the pharmacoeconomicspatient need.
What patients tolerate, what ourgoals are, but I hope everybody
will, will remember and pleaseshare with me this view that the
higher the risk, the lower, wewanna take.
(39:10):
The L D L.
The evidence is compelling thatlower LDLs lead to reduced rates
of event and re reduced rates ofdisease progression.
Ben (39:22):
Dr.
Nien, that's you said a couplekey things there that we'll
highlight and, and I thinkfirst, second, third line is
statins.
And, and like you just said,even just this past week, I've
gotten asked by some of myinterns colleagues is, is there
ever a too low in, in some highrisk primary prevention and
secondary prevention?
And I think you.
You clearly state that and we'llhave links to some of these
(39:43):
landmark trials, including yourinitial New England Journal
piece about Rozi, RosieGlitazone.
Yeah.
To to end this is more on like aphilosophical topic.
Yeah.
Dr.
Nisson, I've had the pleasure ofworking with you for now, three
and a half, four years, roundingin the unit with you for several
hours each day, and, and I've,I've kind of noticed and, and
heard some of your stories, but.
(40:05):
You know, after, after kind ofseeing through different eras in
cardiovascular medicine, beinga, a major player in that, you
know, we have a lot of peoplewho are listening who are early
career and some who are reallymotivated mid-career and late
career docs.
What motivation would you givethem?
What, what words of advice wouldyou give them on how to stay on
top of things?
(40:25):
How to keep interested.
And, and how to push your careerforward.
How, what would you give like a,a last parting statement?
Well,
Steven (40:33):
I could tell you is there's no, there's no easy
route, you know, and get to workearly, you know, keep your, your
eye on the literature you know,dream big.
Never believe that you can'taccomplish something.
I'm gonna tell you one finalstory.
(40:54):
There was a, a guy who at thetime was a fellow who got the
idea that may, he saw me givingnitropress eye to patients with
aortic stenosis, and he said,shouldn't we study that in an R
C T?
So he designed a 25 patient, R Ct.
That we did in the C C U showedthat Nitro Proxide made people
(41:15):
with critical as better, and hegot it published as a fellow in
the New England Journal ofMedicine.
Dream Big.
Kanny (41:25):
That's fitting Steve.
Yeah, that was my only questionis does Ben really show up for
rounds in the C C U at four 30when you get there?
Cuz I have a hard time
Steven (41:33):
believing that.
Well, what happens of course, isthe fellows know what time I get
up, so they always make surethey get there a little before I
Ben (41:40):
do.
I'll tell you those weeks.
Breakfast is just earlier.
That's it?
Yeah.
Steven (41:46):
I start rounds at seven only because the residents would
be furious.
It would be if I made'em roundat six, I just assume round at
6:00 AM
Ben (41:55):
That's so funny.
Hey, Dr.
Nissen thanks so much.
Thank you for joining today'spodcast.
For more information about thespeakers or the topics, please
go to Ohio acc.org,
Welcome to the Cardio OhioPodcast, a production of the
Ohio Chapter of the AmericanCollege of Cardiology.
This is Can Greyal in Columbus,Ohio.
This is Ben Allen CherryCardiovascular Imaging fellow
from Cleveland, Ohio.
More information on the podcast,including past episodes, is
available@ohioacc.org.
(00:27):
And now for today's,
Ben (00:31):
All right.
Welcome back to the Cardio Ohiopodcast.
I'm here along with my co-hostKenny Graywall.
We have a very special guesttoday, Dr.
Steve Nissen, who is chiefAcademic Officer at the CDE and
Arnold Miller Family Heart andVascular Thoracic Institute at
Cleveland Clinic.
(00:51):
But I would be remiss to try tostart to name all of the hats he
has worn in the past.
More importantly, one thing hedid with me is he was part of
the recruitment when I went toCleveland Clinic as a fellow.
And I have rounded with Dr.
Nissen in the I C U severaltimes and, and learned a lot
from Dr.
Nissen.
So I wanna introduce Dr.
Steven (01:10):
Nissen.
Well, thank you very much forthat nice introduction.
Ben (01:15):
so, Dr.
Nisson, we wanted to start withfirst, just to let the audience
kind of hear a little more aboutyour story.
We, we asked for like a littleshort biography of our of our
guests and, and kind of just ifyou just take us through an, a
whirlwind tour of, of sort ofthe places you've been since
medical school the hats you'veworn, especially at the
Cleveland Clinic and what you'recurrently doing now.
Steven (01:37):
Okay, so very quickly I went to University of Michigan
Medical School and I then wentto the University of California
Davis for internal Medicineresidency.
And it turns out there I met aninteresting character, a guy by
the name of Anthony Daria.
Tony Daria, who many of youknow, went on to become editor
(01:58):
of the Journal of the AmericanCollege of Cardiology.
But You know, he recognized thatI had an interest in academic
cardiology and so he offered totake me with him when he took
the job as chief of cardiologyat University of Kentucky, and I
went to University of Kentuckyand I did my fellowship there
(02:19):
very quickly.
I was a two year, it wasnominally a two year fellowship,
but frankly it was more like aone year fellowship.
And then I was made the directorof the coronary intensive care
unit, which I.
Loved and did that for a numberof years.
Did some wild and crazy thingsin Kentucky.
Started a helicopter service andused to fly out almost every
(02:41):
night and pick up acute mi, give'em thrombolytics in the, in the
field, in rural Kentucky, andfly'em back to Lexington for
their, their cath, which wasacquired at 90 minutes In those
days, per protocol.
I then got recruited to theCleveland Clinic by the then
chairman Eric Topel as vicechair, and came to the clinic in
(03:05):
the early 1990s, 92, 93.
And while I had been atKentucky, I had developed
intravascular ultrasound, haddone some of the initial work
with it and brought thetechnology to Cleveland and
began to refine it.
Developed a core imaginglaboratory to make measurements.
(03:28):
And while everybody else in thefield thought that intravascular
ultrasound ivus would be used toguide interventions, I thought
it was ideally suited to measureatherosclerosis.
And so I convinced a companythat had this new drug called
Lipitor and that we could showwhether or not.
(03:54):
Attaining a lower cholesterollevel could reduce the
progression of coronary disease.
And so in about 1997, wedesigned the reversal trial.
We finished it and published itin 2003.
It was got a huge amount ofattention because it showed that
(04:17):
lower levels of L D L wereassociated with less.
Disease progression.
It actually ended up on thefront page of the New York
Times, and I then went on with ateam that I had developed here
at the Cleveland Clinic to do an11 more intravascular ultrasound
trials over the next decade orso.
(04:40):
And that for me was an entryinto the larger world of large
randomized clinical outcometrials.
And so it was just one step at atime.
Pull yourself up by yourbootstraps, do the work, you
know, publish it and standbehind it.
And hopefully if you do that,good things will come your way.
Ben (05:05):
That's a that's an awesome recap, Dr.
Nissen.
And I think we're gonna have aseparate podcast for the
helicopter stories
Steven (05:10):
for sure.
Oh my God.
I can tell you war stories thatyou wouldn't even believe.
Kanny (05:17):
So Steve I know you've been also a, as you progressed
from the IVUS trials into someof the other randomized trials
and lipids and other topics, youkinda led.
This this kind of change in howwe approach trials in terms of
safety events with yourexperience with Glitazone.
Yeah.
And we were just curious likehow you got interested in that
specific aspect of clinicaltrials and which has now kind of
(05:40):
become a standard in terms oflooking at, safety
Steven (05:42):
outcomes.
Well, it's actually interestingbecause, you know, you have to
be prepared.
For this sort of finding.
You know, I don't, I didn't golooking for any of this, but in
the year 2001, I got asked bythe F D A to serve on the
Cardiorenal advisory panel, andthe first panel I attended was a
(06:04):
review of a gastrointestinalclaims for a drug known as
Vioxx.
And I looked at the data, youget thousands of patients of
data from the F D A, and I sawthat in every study.
There seemed to be morecardiovascular events in the
(06:25):
people that got RO coxibcompared with other drugs.
And so we collected all of thedata that we could and.
We published a manuscript inJAMA that raised questions about
the safety of, of Roha.
Coxib, otherwise known as Vioxx.
(06:46):
Took a terrible beating.
It was really awful.
Actually the study was led byDeb Mukerjee, who was a
interventional fellow at thetime and now chief of cardiology
at an institution in, in Texas.
And, You know, we got beat up bythe pharmaceutical industry, but
we stu stuck to our guns, andfour years later, the drug was
(07:09):
withdrawn for unequivocal harm.
Then in 2007, I had concerns.
About the diabetes drugglitazone known by the brand
name of Avania.
I had noticed that in clinicaltrials, again, published trials
(07:29):
were relatively limited, thatthe cardiovascular events seemed
to be trending in the wrongdirection and the drug was being
marketed for cardiovascularbenefits, and it didn't make any
sense to me.
So I went looking for more data.
And there was almost nothing,and then I hit a gold mine.
(07:51):
It turns out that the formerattorney General of New York
State Elliot Spitzer, who laterfell from Grace, but Elliot
Spitzer sued the maker of RosaGlitazone GlaxoSmithKline
because the company had hiddendata on hazards.
(08:14):
From their, one of theirantidepressant drugs in teens
and children, teens, youngadults, where there was
increased suicide andsuicidality.
The settlement was for$1, butwith the requirement that the
company post all of the resultsof their clinical trials on a
(08:35):
website.
The website was fairly wellhidden, but I found it.
And I downloaded all of the dataon Rosa Glitazone.
There were 42 clinical trials,35 of which were unpublished,
and my lead statistician, KathyWolski, and I huddled in my
(08:59):
office for a couple of days,wrote a New England Journal of
Medicine manuscript.
Which was a meta-analysis of allthe available data that we had
access to because of thatprevious lawsuit.
Please keep in mind that upuntil this point in time, a
company could do a clinicaltrial.
They didn't like the results.
(09:19):
Nobody ever got to see it callednegative publication bias, and,
and a lot of academics wentalong with that.
Well, what we saw was a 30 to40% increase in.
Myocardial infarction and asimilar increase in
cardiovascular death withglitazone compared with other
(09:41):
drugs.
When that thing hit the, hit thestreets, you know, the New
England Journal of Medicinereviewed it and published it in
21 days, and when it came out,headline news, you know, it was
just incredibly intense.
But the result, Was that at an fd A advisory board meeting in
(10:04):
2008, I proposed that they nolonger approved diabetes drugs
simply because they lower abiomarker blood sugar, that they
had to do cardiovascular outcometrials as a condition of
obtaining approval.
And we worked out a, a system,you know, I proposed it.
(10:25):
The panel agreed the f d A panelagreed and it became a.
The rule and in the years sincethen, all of the trials, you
know, with the SGLT twoinhibitors, the GLP one
agonists, all of the data thatcame out was a result of Seeing
a signal with Rosa Glitazoneacting on the information, being
(10:50):
decisive about writing up themanuscript and publishing it and
standing behind the findings.
And you know, so there were twopretty large, very large, I
mean, headline news, drug safetyissues.
You know, I got accused by somepeople who, for various reasons,
wanted to believe it, that I wassomehow.
(11:11):
An anti-drug industry, which ofcourse is not the case.
We need a great drug industry todevelop new therapies for
patients, but we have to beprepared to tell people what
works, what doesn't work, andwhat's harmful, and to provide
equal weight.
To the findings, regardless ofwhich direction they
Ben (11:34):
go.
And, and Dr.
Nissen, I'll just jump in therebecause I remember hearing the
story as a first year fellowwhen we were rounding in the
unit, and I, I couldn't believeit.
And I wanted to highlight forour listeners that.
You know, indirectly youprobably had a lot of
pharmaceutical mafia people comeafter you, but at the same time,
the this, this sort of action iskind of why we have SGLT two s
(11:57):
and GLP one s because of thatpush for having cardiovascular
outcomes.
So, I mean, you're saying thestory, but I think it's even
bigger than, than this becausethis has shaped some of our
newest drugs that we use in allof these patients.
Steven (12:11):
No one would be able to use these drugs if we hadn't
required the trials because youknow, the pharmacy benefit
managers would say, well, whyshould we pay for a drug when
all it does is lower bloodsugar, the same way of
sulfonylurea or any other druglowers blood sugar.
So it turned out it actuallyhelped the industry, but it
helped patients.
That's what really counts.
(12:32):
And you know, I proudly stoodbehind the data.
It was a very difficult timebecause you know, I can tell you
that if you do take on amulti-billion dollar industry,
they're gonna come after you andyou better have thick skin.
And you better be willing tostand your ground.
But I'm pleased with how it allworked out.
(12:55):
And I do think you're right.
There have a number of peoplehave written about what
happened, and in fact, there was172 page report from the US
Senate after they had held abunch of hearings that goes into
all of the gory details, one ofwhich was unbelievable that when
we submitted the manuscriptwithin 24 hours, one of the
(13:18):
reviewers.
Who had a financial relationshipwith GlaxoSmith Klein gave him a
copy of the manuscript while itwas in review, which is wow
considered highly unethical.
And as a result the company knewit was coming.
And they plotted their strategyon how to character assassinate
(13:42):
The two authors myself and, andMs.
Wolski, and, you know, this allcame out in the Senate report
that the, the, the senatorsdiscovered with subpoenas the
actual facts that had gone fromthe, from the reviewer to the
company.
That had given them a copywithin hours of its submission
(14:05):
of the manuscript I'd submittedto the New England Journal.
Kanny (14:10):
That is a, that's a tremendous story.
We, we are familiar with it, butyeah.
But it's great to hear, it'sgreat to hear her firsthand
accounting of it though.
That's tremendous.
So, so Steve, before we spendthe last 10 or 15 minutes
talking about some of the newer.
Trials.
Yeah.
I did want to ask you, you'vespent, you have so much
experience conducting trialsthat have been so seminal, and
(14:33):
of course you review trials aswell for some of our young,
early practi, early careerpractitioners, our fellows in
training our nursepractitioners.
as you know, the, the medicalliterature has just exploded and
specifically the cardiovascularliterature.
So when you, when you approach atrial as a reader, as a
clinician in your clinician hat,And you're trying to determine,
(14:53):
the relevance and how it mayapply to your patients.
Are there a few things you focuson to help kind of, clear the
wheat from the shaft and figureout which, which studies really
are gonna have impact and, and,and contain actionable
information?
How do you approach, you know,well, that's
Steven (15:10):
a great question.
You, you certainly have to divedeep and I find that some of the
best information.
Is actually in the supplementthat almost nobody else reads,
and I'll give you an example ofthat.
You know, the Reduce Itmanuscript came out with a Casa
(15:31):
Pyl, otherwise known as vascepa,and it just seemed too good to
be true.
And so I'm looking at thesupplement and and buried on the
last page of the supplement ornearly the last page, I find a
single line that shows whathappened to high sensitivity C
(15:52):
reactive protein in the twotreatment arms.
And it turns out that in thecontrol arm, which was a mineral
oil placebo, there was a 30 pluspercent increase.
C-reactive protein unheard of.
And what that led to was aseries of investigations, and I
(16:15):
think there are a lot of peoplewho now agree with me that
basically it's a false positivestudy that instead of using a
neutral placebo, the trial useda placebo that was toxic.
And so the apparent benefits ofACO ethyl were actually due to
the toxicity of the control ofthe placebo and not to the
(16:37):
benefits.
If I hadn't looked deeply intothat supplement, And everybody
else missed it.
Nobody.
Nobody really saw it.
And then later on, Paul Rickerdid an analysis of blood samples
from the trial.
And every inflammatory markeryou can imagine went.
(16:58):
Incredibly bonkers up with themineral oil treatment group.
And so it's a classic example ofa drug that got a, got a label
from the F D A.
It's widely used.
It is not, it does not producefavorable effects.
It's a false positive study.
Yeah,
Ben (17:19):
and I think Dr.
Nissen, that that point ofdiving into the.
Like the details, thesupplemental indices, it's, I
guess the challenge is there'sso many of these clinical trials
that come out and in general,cardiology, you are spanning
prevention, imaging, when tointervene on patients.
How do you, is there a guide youuse, like do you follow certain
(17:40):
journals specifically?
How, what would be your words ofadvice for, for the general
practitioner to make surethey're staying up
Steven (17:46):
to date?
Well, I think first of all, thetier one journals, which are,
you know, jama, new EnglandJournal and the Lancet a lot of
the most weighty researchappear, not all of it, but a lot
of very most important researchappears in those three journals.
And I try to look at them and Ithink there is time for most
cardiovascular practitioners to,to read.
(18:09):
The cardiovascular studies thatare published in those top three
journals, I mean, that's justnot a big lift.
And, you know, look, I work veryhard, you know, I'm one of the
oldest people in our department,but I'm the first one there in
the morning.
I get there at four 30 or fivein the morning every day, off
and on weekends.
(18:31):
I spend the time that I have asproductively as I can, and I do
read the literature carefully soI can stay informed, and it
helps you pose the questions.
That you wanna ask?
You know it's kind ofinteresting because there are
always people that are gonnapush back.
I was just remembering againabout the whole glitazone
(18:55):
controversy.
And when I propose requiringoutcome trials for diabetes
drugs, many people in thediabetes community looked me in
the eye and they said, if you dothis nien, we will never have
another diabetes drug.
Because no company's gonna makethe investment in doing the
outcome trials.
(19:15):
Well, you can see what'shappened since then up just a
proliferation of very, very goodtrials.
Ben (19:23):
Yeah, I definitely agree that that was a courageous move.
And, and kind of before we jumpinto now, the, the current lipid
trials, including clear Yeah, I,I did have a question.
Sometimes we have patientslisten and.
I think it's, it's sometimes aan art to explain to them the
importance of enrolling inclinical trials with the chance
(19:44):
that they get a placebo.
Obviously patients want to betreated.
How, how have you kind ofnavigated that as somebody who's
run several clinical trials?
Yeah, yeah.
Even for example, in the mavacampton trials Yeah.
That you've been involved in.
How do you, how do you kind ofapproach patients in that way?
Steven (20:02):
Well, first of all, patients who volunteer for
clinical trials, it is a nobleendeavor and they do so for very
good reasons.
They do so they will say to us,we know this may not help me,
but if it helps somebody else, Ithink it's worth it.
The other thing that is reallyamazing, there have been
multiple studies published thatpeople that are in the placebo
(20:25):
harm.
Of randomized trials do much,much better than the general
population.
Why is that?
It's because they get very goodmedical care.
They get managed to, you know,with state-of-the-art control of
their risk factors.
They're seeing peoplefrequently, you know, the nurse
coordinator and or the, theprincipal investigator at the
(20:48):
local site.
And so they do better.
And so being, just being in aclinical trial gives you an
advantage over people who arenot in a clinical trial.
And that's the truth.
There's lots of studies thatshow that.
Ben (21:04):
Yeah.
And I can imagine once, oncepatients wrap their head around
that, but also if they have thecourage to continue to, to be
somewhat altruistic, it reallyshapes the field because as much
as the, the clinical trial isrunning the trial, it's the
patients who are involved whopush it forward as well.
You bet.
So, Dr.
Ni, can you just tell us becauseyou noted this, Difference in
(21:28):
the omega-3 trials.
Can you just tell us how fromthe Cleveland Clinic group,
there was a, a, not a rivaltrial, but a, it was sort of
proof of concept trial that wasconducted as well?
Yeah.
How did you kind of
Steven (21:41):
start that?
Well that was started actuallyour trial was with a different
product.
Very similar in many ways, to aCasa Pyl or vascepa.
It was just a little differentformulation and we ran the
trial.
It was, it was actually largerthan reduce it and it showed no
(22:02):
benefit.
There was just nothing and.
We said to ourselves, I, youknow, this was, this was
finished just a few months afterreduce it.
We said, how can one fish oilthat does low risk triglycerides
a little bit, does a few otherthings, show a 25% reduction in
(22:24):
morbidity, mortality, andanother product that is almost
the same chemically show zerobenefit.
Something had to be wrong there.
And the, the, of course, the, I,I had a very good idea what it
was.
And it was the, the problem withthe placebo we used and we knew,
(22:48):
by the way, that mineral oil wasprobably toxic when we designed
the strength trial.
We did was, again, similar insize, you know, 12,000 patients,
I mean bigger in size, 12,000patients.
We chose corn oil as the placebobecause we thought corn oil was
about as neutral as you can get.
(23:08):
We thought olive oil wasbeneficial.
We knew that there were issuesaround mineral oil, so we chose
something deliberately.
That was neutral and there wasno difference between corn oil
and the same four gram dose thatwas used and reduce it with just
a little bit different product.
(23:30):
And so at the end of the day, itjust didn't seem possible that
these two trials could havecompletely opposite results.
Something else had to explainthe differences.
Kanny (23:44):
Yeah.
Thanks Steve.
That that makes sense to set thestage for our last 15 or 20
minute discussion about, youknow, clear and.
Other agents.
I'm, I'm really fascinated by,you know, the concept of statin
intolerance.
I was reviewing some of yourprevious articles about that in
the last several years, and I, Ithink you have a very
(24:05):
interesting definition of it.
And one thing you raised in oneof your, your editorials a few
years back was a concept thatperhaps with statin trials, you
know, the fact that patientshave to be recruited into these
studies, that somehow we'reselecting a group of patients
who are less prone.
To the side effects because, youknow, just like you, I'm a
(24:25):
clinic clinician who's in clinicalmost every day taking care of
patients.
And you know, the concept ofstatin intolerance comes up
almost daily, multiple timeswith our patients.
And of course, when you look atthe literature of, of the
incidents, there's such adichotomy between what we see in
the real world.
And it looked like in some ofyour editorials, you addressed
that.
So I was wondering if you couldjust review how, how you put
(24:48):
that in perspective with some ofyour
Steven (24:50):
patients.
Well, first of all, it is a verycontroversial topic.
You know, there is a group inEurope, in, in the UK that
thinks it doesn't exist.
There are other people thatBuild their entire careers on
the treatment of patients with,with statin intolerance.
You know, my, I have a verypragmatic view of this.
(25:12):
There's two things I reallythink people should know.
One is that most of the clinicaltrials that have been conducted
have a run-in period where youget the drug.
And, you know, if you have aninability to tolerate the drug,
then you're not randomized.
So you have this, this run-in,in advance of actually
(25:36):
conducting the trial.
And so you remove from the studyall the people that are statin
intolerant and the other QuestOther issue is really a very
practical one.
If a patient comes in yourclinic Kenny and says, You know,
I have tried the statins, I'vetried multiple statins.
(25:58):
I can't tolerate the statins andI won't take a statin.
And they have a very high L D Lin their, you know, they've had
a previous event.
What are you gonna do?
You, you can't force a patient,take a drug they don't wanna
take.
And so we have to have practicalalternatives, even if you think
that it's in their head fromthat.
(26:19):
For them it's real.
Kanny (26:22):
Absolutely.
Well, thanks to you and othertrialists.
Fortunately we we're increasingour armamentarium now.
Yeah.
So that so that we do have manymore options.
Ben (26:34):
we're gonna focus on the newest on his newest trial, the
clear trial.
I'm gonna just give a briefsummary so that Dr.
Nissen doesn't have to startfrom, from ground zero here.
The clear trial published in NewEngland Journal was randomized
about 13,000 patients.
Who are at high risk foratherosclerotic cardiovascular
disease and who are unable totake more than a low dose statin
(26:56):
to either the placebo arm or beoacid.
And that's the drug that isbeing tested.
And so they randomized 13,000patients.
And their primary outcome was a,a composite, the standard, major
adverse cardiovascular event,composite of death from CV
causes non-fatal mi, non-fatalstroke and need for coronary
(27:16):
revascularization, and theyfound a a, a significant
reduction.
In Mace.
And, and kind of the, the mainthings that we thought that this
was so applicable clinically wasbecause it, it adds to the
armamentarium for our primaryprevention patients who are at
high risk and don't have optionsbecause of intolerance.
And so from there, just withthat background, Dr.
(27:39):
Nissen I kind of just wanted toask you from the, from the
get-go, what did you foreseewhen you were initially starting
the design of the trial?
Well,
Steven (27:47):
we knew that beo acid is a pro-drug.
It's not active in peripheraltissues.
It gets taken up by the liverwhere it gets converted to its
active form.
And so if it's not active inperipheral tissues, it can't
cause the kno myalgias that manypatients complain about when
they take statins.
(28:08):
And we had pretty good evidencefrom smaller trials that it
didn't seem to produce the kindof musculoskeletal problems and
statins.
Produce.
So it made sense then to studythis drug in statin intolerant
patients.
Now, just wanna make sure youunderstand that about 80% of the
patients were on no statin.
They couldn't tolerate any.
(28:30):
And about you know, 20% or so,were on less than the lowest
approved dose of a statin, likeon 10 milligrams of atorvastatin
twice a week.
That sort of thing.
So these are really people thatare statin intolerant and we
made'em sign a statement thatthey would not take a statin
(28:51):
even though they knew statinscould reduce their risk of heart
attack, stroke, or death.
So we did this in an ethicalway.
I thought it was very importantto do that.
And we were able to find at1,250 sites in.
You know, something like 32countries the patients were
(29:12):
enrolled and, you know, we'vewent on for a number of years.
We followed them for about 41months.
And of course, there's nothingin the world quite like
unblinding, a trial you'veworked on for many years and
finding out whether it worked orit didn't work.
Kanny (29:33):
And I, I know that the trial did include almost 50%
women, which is nice to see aswell.
Yeah.
So I was curious though, you dohave kind of a mix of primary
and secondary preventionpatients in the study.
Have you analyzed anydifferential effect in, in those
two groups, those with known c ad and those with, with risk
(29:53):
factors
Steven (29:54):
only?
I thought you'd never ask.
So you have to come to the a d Ameeting.
It's on the program where we aregoing to present detailed
results in the 30% of patients,4,200 patients.
They were primary prevention.
They had high risk factors, butthey'd never had an event.
(30:15):
And if you looked reallycarefully at the supplement, you
will notice that there appearedto be a more favorable effect in
the patients that were in theprimary prevention strata than
those that were in the secondaryprevention.
We're gonna tell you a lot moreabout that.
I'm gonna present it at ada.
(30:36):
And it will be simultaneouslypublished in a major journal.
Ben (30:43):
And I think that's, that's good.
That's the hook right there, Dr.
Nissen.
And also another plug for youfor us to take a look at the,
the depths of these articles,including the supplementary
indices.
Yeah.
When you, when you talk aboutbedo acid, a lot of, a lot of
what people say about statins isthis pluripotent effect
including on anti-inflammation.
(31:04):
And c r p has been used as a, asa marker for this.
Can you just help us as, as faras statins, we kind of
understand some of that.
But as far as beo acid, what'sits relationship to inflammation
that you found in the trial?
Steven (31:15):
Well, keep in mind that beo acid works in the same
pathway as statins, butupstream, and it has quite
intense anti-inflammatoryeffects.
We got about the same amount ofreduction in high sensitivity C
R P.
As we got reduction in L D Lcholesterol, so it has two
(31:36):
potential ways to benefitpatients, both as an
anti-inflammatory.
And we now know thatanti-inflammatory drugs like
Colchicine or Kinumab do havecardiovascular benefits.
And of course, we've known for along time that L D R reduction
has benefits.
Baic acid does both.
What we didn't study.
(31:57):
And I wish we could have, but wecouldn't for a lot of regulatory
reasons, is the drug isavailable, Beto acid, both as
monotherapy and in combinationwith ezetimibe.
The combination with Ezetimibeproduces a 35 to 40% L D L
reduction.
It's about the same as 40milligrams of simvastatin, and
(32:19):
so we can get a pretty robust LD L reduction with that
combination without having togive a statin to those patients
that simply won't or can't takea statin.
Ben (32:34):
Yeah.
So I think that that's awesomethat that offers another option.
Yeah.
Now to, to speak to this pointthough what has been brought up
is something, something aboutcholelithiasis, something about
gout.
Yeah.
As far as the, the true sideeffects, because we know what
statins cause.
How would you frame that fromwhat you've seen in the, in the
patient outcomes and, and maybejust how you would translate
(32:55):
that clinically.
Do we use it in patients withgout already or use it with
caution, et cetera?
Yeah,
Steven (33:00):
I would be very careful and probably I would not use it
unless I really felt I had noother option in patients with a
strong history of gout.
Unless, of course they had beenon a uric acid lowering agent
for some time and had very good,you know, low uric acid levels.
Those people I would be okaywith.
(33:21):
But, you know, I would worryabout triggering gout.
Now look, if you, if you wannatrade off gout, Versus a heart
attack, I'd kind of take a goutattack any day of the week.
Having said that, you know, wedon't want to be cavalier about
these things.
We had not previously seen csis,but there was an excess, about
1% excess of colonese.
(33:45):
In the Baic acid group, youknow, again, it was generally
not something that led tosurgery or sepsis or anything
like that, but it was an excess,and people need to be aware of
that.
Look, let's be very clear, thereis no such thing as a free
lunch.
Every drug we give patients haspros and cons.
(34:08):
It's important, I think, forclinicians to know the upside.
To know the downside and to makean educated decision with the
patient at the table, so-calledshared decision making.
Lay out the risks, lay out thebenefits, make a decision
together on what direction togo.
Kanny (34:29):
Steve I was also there in the audience at a ACC C when you
presented this to muchexcitement.
I, I know there were, there wasone question asked at that time
about the fact that, you know,you had a.
Combined out outcome, not amortality benefit directly.
Yeah.
And yeah, and you know, I'mwondering do you think that's
relevant or do you think thefact that most likely this is
(34:51):
gonna be used in combinationwith Ezetimibe and further LDL
lowering, and of courseEzetimibe has pretty good
evidence base behind it now, doyou think that makes the
mortality issue a little lessrelevant?
Steven (35:01):
Yeah.
Okay.
It's not irrelevant.
It's highly relevant, but here'sthe issue.
Both large PCSK nine inhibitortrials, one of which was 27,000
patients had absolutely nobenefit on mortality with a 50%
L D R reduction.
Almost all the modern trials insecondary prevention patients
(35:25):
have not shown a reduction inmortality.
We didn't see it for Alloc, forEvolocumab.
You know, I could go on and onand on about the trials that did
not show a death benefit.
Why is that?
It's because of everyonelistening to this podcast.
We've become very good attreating people with acute mis.
(35:49):
People don't die of acute MIvery often anymore.
They may die.
7, 8, 10 years down the road.
Or they may ultimately later ondevelop heart failure, but they
don't die in the short run.
And so I don't think we're gonnasee lipid lowering therapy even
with these very powerful L D Llowering drugs.
(36:12):
Reduce mortality.
We didn't see with baic acid, wedidn't see it with PCSK nine
inhibitors.
It's just too much of a reach inthe contemporary era.
Kanny (36:24):
Yeah, and I think that does make complete sense, so
thanks for clarifying.
So as we kind of put this studywith Bedo acid in perspective
with so many other, you know,existing or agents that are on
the way, I'm just curious tofinish up in the last five
minutes or so how you approach,you know, all of the statin
(36:46):
alternatives now in your mind.
Obviously we know that forprimary, excuse me, for
secondary prevention patients,we're always gonna start with a
high dose statin.
And we know, we know we havevery good data about target
LDLs.
But how would you rank this drugwith say, PCSK nine inhibitors,
which you just mentioned, aswell as Zein and some of the
(37:07):
others as you approach a patientwho say statin intolerant.
And then as a follow up, apatient who doesn't get to go.
On the maximum statin dose theycan tolerate.
Steven (37:18):
Well, Kenny, you said something interesting, which of
course, which I agree with,which is that we have good idea
of what target staff for L D L.
Unfortunately, we haven't beenable to convince our guideline
writers that that's the, thatthat's the case.
But having said all of that I dobelieve that lower is better.
And the higher the risk thepatient, the lower you wanna go.
(37:41):
Statins are the first line drug.
They're the second line drug,and they're the third line drug.
And we try, try and try again.
If we get'em on, get patients ona statin and their l d L is
still above where we want it.
The natural thing to do is toadd ezetimibe because it's
generic, it's inexpensive, it'svery well tolerated, very safe.
(38:05):
There will be people that willnot get there.
With adding ezetimibe, and theywill need a PCSK nine inhibitor.
And that includes now lyran,which is a, you know, very
attractive drug because it's solong acting that you only have
to give it twice a year ifpeople cannot tolerate
(38:27):
evidence-based.
Doses of statins, well then wehave alternatives like beo acid
or beo acid with ezetimibe, andif they need a lot of L D L
reduction, then even beo acidwith ezetimibe may not be
enough, and we may need to go toa PCSK nine inhibitor.
Here's what's really fantastic.
(38:50):
We have a lot of tools in thetool chest, and we can pick them
based upon the pharmacoeconomicspatient need.
What patients tolerate, what ourgoals are, but I hope everybody
will, will remember and pleaseshare with me this view that the
higher the risk, the lower, wewanna take.
(39:10):
The L D L.
The evidence is compelling thatlower LDLs lead to reduced rates
of event and re reduced rates ofdisease progression.
Ben (39:22):
Dr.
Nien, that's you said a couplekey things there that we'll
highlight and, and I thinkfirst, second, third line is
statins.
And, and like you just said,even just this past week, I've
gotten asked by some of myinterns colleagues is, is there
ever a too low in, in some highrisk primary prevention and
secondary prevention?
And I think you.
You clearly state that and we'llhave links to some of these
(39:43):
landmark trials, including yourinitial New England Journal
piece about Rozi, RosieGlitazone.
Yeah.
To to end this is more on like aphilosophical topic.
Yeah.
Dr.
Nisson, I've had the pleasure ofworking with you for now, three
and a half, four years, roundingin the unit with you for several
hours each day, and, and I've,I've kind of noticed and, and
heard some of your stories, but.
(40:05):
You know, after, after kind ofseeing through different eras in
cardiovascular medicine, beinga, a major player in that, you
know, we have a lot of peoplewho are listening who are early
career and some who are reallymotivated mid-career and late
career docs.
What motivation would you givethem?
What, what words of advice wouldyou give them on how to stay on
top of things?
(40:25):
How to keep interested.
And, and how to push your careerforward.
How, what would you give like a,a last parting statement?
Well,
Steven (40:33):
I could tell you is there's no, there's no easy
route, you know, and get to workearly, you know, keep your, your
eye on the literature you know,dream big.
Never believe that you can'taccomplish something.
I'm gonna tell you one finalstory.
(40:54):
There was a, a guy who at thetime was a fellow who got the
idea that may, he saw me givingnitropress eye to patients with
aortic stenosis, and he said,shouldn't we study that in an R
C T?
So he designed a 25 patient, R Ct.
That we did in the C C U showedthat Nitro Proxide made people
(41:15):
with critical as better, and hegot it published as a fellow in
the New England Journal ofMedicine.
Dream Big.
Kanny (41:25):
That's fitting Steve.
Yeah, that was my only questionis does Ben really show up for
rounds in the C C U at four 30when you get there?
Cuz I have a hard time
Steven (41:33):
believing that.
Well, what happens of course, isthe fellows know what time I get
up, so they always make surethey get there a little before I
Ben (41:40):
do.
I'll tell you those weeks.
Breakfast is just earlier.
That's it?
Yeah.
Steven (41:46):
I start rounds at seven only because the residents would
be furious.
It would be if I made'em roundat six, I just assume round at
6:00 AM
Ben (41:55):
That's so funny.
Hey, Dr.
Nissen thanks so much.
Thank you for joining today'spodcast.
For more information about thespeakers or the topics, please
go to Ohio acc.org,
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