0:05

Welcome to the Cardio Ohio Podcast,

0:07

a production of the Ohio Chapter

0:10

of the American College of Cardiology. This

0:12

is Can Greyal in Columbus, Ohio.

0:15

This is Ben Allen Cherry Cardiovascular

0:18

Imaging fellow from Cleveland, Ohio.

0:20

More information on the podcast, including

0:23

past episodes, is [email protected].

0:27

And now for today's,

0:31

All right. Welcome back to the Cardio Ohio

0:33

podcast. I'm here along with my

0:35

co-host Kenny Graywall. We

0:38

have a very special guest today,

0:40

Dr. Steve Nissen, who

0:42

is chief Academic Officer at

0:45

the CDE and

0:47

Arnold Miller Family Heart and Vascular Thoracic

0:49

Institute at Cleveland Clinic. But

0:51

I would be remiss to try to start to name

0:53

all of the hats he has worn in the past. More

0:56

importantly, one thing he did

0:58

with me is he was part of the

1:00

recruitment when I went to Cleveland Clinic as a fellow.

1:03

And I have rounded with Dr. Nissen

1:05

in the I C U several times and,

1:07

and learned a lot from Dr. Nissen. So I wanna

1:09

introduce Dr.

1:10

Nissen. Well, thank you very much for

1:12

that nice introduction.

1:15

so, Dr. Nisson, we wanted to start with first,

1:17

just to let the audience kind of hear

1:19

a little more about your story. We, we asked for

1:21

like a little short biography of

1:24

our of our guests and,

1:26

and kind of just if you just take us through an,

1:29

a whirlwind tour of, of sort of the places

1:31

you've been since medical school the

1:34

hats you've worn, especially at the Cleveland Clinic and what

1:36

you're currently doing now.

1:37

Okay, so very quickly I

1:40

went to University of Michigan Medical School and

1:43

I then went to the University of California Davis

1:47

for internal Medicine residency. And

1:49

it turns out there I met an interesting

1:51

character, a guy by the name of Anthony

1:53

Daria. Tony Daria, who many of

1:55

you know, went on to become

1:57

editor of the Journal of the American College of Cardiology.

2:00

But You

2:02

know, he recognized that I

2:04

had an interest in academic cardiology

2:07

and so he offered to take me with him

2:10

when he took the job as chief of cardiology

2:12

at University of Kentucky, and

2:14

I went to University of Kentucky and

2:17

I did my fellowship there very quickly.

2:20

I was a two year, it was nominally a

2:22

two year fellowship, but frankly it was more like

2:24

a one year fellowship. And

2:26

then I was made the director

2:28

of the coronary intensive care unit, which I. Loved

2:32

and did that for a number of years. Did

2:34

some wild and crazy things in Kentucky.

2:37

Started a helicopter service and

2:39

used to fly out almost every night

2:41

and pick up acute mi, give

2:44

'em thrombolytics in the, in

2:46

the field, in rural Kentucky,

2:48

and fly 'em back to Lexington for their,

2:51

their cath, which was acquired at 90

2:53

minutes In those days, per protocol.

2:56

I then got recruited to the Cleveland Clinic

2:59

by the then chairman Eric Topel

3:01

as vice chair, and came

3:04

to the clinic in the early 1990s,

3:07

92, 93. And

3:10

while I had been at Kentucky, I

3:12

had developed intravascular ultrasound,

3:15

had done some of the initial work with

3:17

it and brought the technology

3:19

to Cleveland and

3:22

began to refine it. Developed

3:24

a core imaging laboratory

3:26

to make measurements. And

3:28

while everybody else in the field thought

3:31

that intravascular ultrasound ivus

3:33

would be used to guide interventions,

3:37

I thought it was ideally suited

3:40

to measure atherosclerosis. And

3:43

so I convinced a

3:45

company that had this new drug called

3:48

Lipitor and

3:50

that we could show

3:52

whether or not. Attaining

3:55

a lower cholesterol level could

3:57

reduce the progression of coronary

3:59

disease. And so in about 1997,

4:03

we designed the reversal trial.

4:06

We finished it and published it in

4:08

2003. It

4:13

was got a huge

4:15

amount of attention because it showed that

4:17

lower levels of L D L were associated

4:20

with less. Disease progression.

4:23

It actually ended up on the front page of the New

4:25

York Times, and

4:27

I then went on with a team that

4:29

I had developed here at the Cleveland

4:31

Clinic to do an

4:33

11 more intravascular

4:36

ultrasound trials over the next decade

4:38

or so. And that for me

4:41

was an entry into the

4:43

larger world of large

4:46

randomized clinical outcome

4:48

trials. And so it

4:50

was just one step at a time. Pull

4:52

yourself up by your bootstraps,

4:55

do the work, you know, publish

4:57

it and stand behind

4:59

it. And hopefully if

5:01

you do that, good things will come your way.

5:05

That's a that's an awesome recap, Dr.

5:07

Nissen. And I think we're gonna have a separate podcast

5:09

for the helicopter stories

5:10

for sure. Oh my God. I can tell you

5:12

war stories that you wouldn't even believe.

5:17

So Steve I know you've been also

5:19

a, as you progressed from the IVUS trials

5:21

into some of the other randomized

5:24

trials and lipids and other topics, you kinda

5:26

led. This this kind

5:28

of change in how we approach trials in terms of safety

5:30

events with your experience with Glitazone.

5:33

Yeah. And we were just curious like how

5:35

you got interested in that specific

5:37

aspect of clinical trials and

5:39

which has now kind of become a standard in terms

5:41

of looking at, safety

5:42

outcomes. Well, it's actually

5:44

interesting because, you

5:47

know, you have to be prepared. For

5:49

this sort of finding. You know, I don't,

5:51

I didn't go looking for any of this,

5:54

but in the year 2001,

5:57

I got asked by the F D A to serve

5:59

on the Cardiorenal advisory panel,

6:01

and the first panel I attended

6:04

was a review of

6:07

a gastrointestinal claims for

6:09

a drug known as Vioxx.

6:13

And I looked at the data, you

6:15

get thousands of patients of data from

6:17

the F D A, and I saw

6:19

that in every study. There

6:22

seemed to be more cardiovascular

6:24

events in the people that got

6:26

RO coxib compared with

6:29

other drugs. And

6:31

so we collected all

6:33

of the data that we could and.

6:37

We published a manuscript in JAMA

6:40

that raised questions about the safety

6:42

of, of Roha. Coxib, otherwise

6:45

known as Vioxx. Took

6:47

a terrible beating. It

6:49

was really awful. Actually

6:51

the study was led by Deb Mukerjee,

6:54

who was a interventional fellow

6:57

at the time and now chief of cardiology

6:59

at an institution in, in Texas. And,

7:02

You know, we got beat up by the pharmaceutical

7:04

industry, but we stu stuck to our guns,

7:07

and four years later, the drug

7:09

was withdrawn for unequivocal

7:11

harm. Then in 2007,

7:15

I had concerns.

7:18

About the diabetes drug

7:20

glitazone known by the brand

7:23

name of Avania. I

7:25

had noticed that in clinical trials,

7:27

again, published trials were

7:29

relatively limited, that

7:32

the cardiovascular events seemed

7:34

to be trending in the wrong direction

7:36

and the drug was being marketed for

7:38

cardiovascular benefits,

7:41

and it didn't make any sense to me. So

7:44

I went looking for more data. And

7:46

there was almost nothing, and

7:49

then I hit a gold mine. It

7:51

turns out that the former

7:54

attorney General of New York State

7:56

Elliot Spitzer, who later fell

7:58

from Grace, but Elliot

8:00

Spitzer sued the maker

8:03

of Rosa Glitazone GlaxoSmithKline

8:07

because the company had

8:09

hidden data on

8:12

hazards. From

8:14

their, one of their antidepressant drugs

8:17

in teens and

8:20

children, teens, young adults, where

8:23

there was increased suicide and suicidality.

8:26

The settlement was for $1, but

8:29

with the requirement that the company

8:31

post all of the results of

8:33

their clinical trials on a website.

8:37

The website was fairly well hidden,

8:39

but I found it. And I

8:41

downloaded all of

8:44

the data on Rosa

8:46

Glitazone. There were 42

8:48

clinical trials, 35

8:51

of which were unpublished, and

8:55

my lead statistician, Kathy Wolski,

8:57

and I huddled in my office for

8:59

a couple of days, wrote a New

9:01

England Journal of Medicine manuscript. Which

9:04

was a meta-analysis of all

9:06

the available data that we had access

9:08

to because of that previous

9:11

lawsuit. Please keep

9:13

in mind that up until this point in time,

9:15

a company could do a clinical trial. They

9:17

didn't like the results. Nobody ever got

9:20

to see it called negative publication

9:22

bias, and, and a lot of academics

9:24

went along with that. Well,

9:26

what we saw was a 30

9:29

to 40% increase in.

9:32

Myocardial infarction and

9:34

a similar increase in cardiovascular

9:37

death with glitazone

9:40

compared with other drugs.

9:42

When that thing hit the, hit the streets,

9:45

you know, the New England Journal of Medicine reviewed

9:48

it and published it in 21 days, and

9:50

when it came out, headline

9:53

news, you know, it was

9:55

just incredibly intense.

9:58

But the result, Was

10:00

that at an f d A advisory

10:03

board meeting in 2008,

10:05

I proposed that they no longer approved

10:08

diabetes drugs simply because

10:10

they lower a biomarker blood

10:13

sugar, that they had to do

10:15

cardiovascular outcome trials as

10:17

a condition of obtaining approval.

10:20

And we worked out a, a system,

10:23

you know, I proposed it. The

10:25

panel agreed the f

10:27

d A panel agreed and it became

10:29

a. The rule and

10:32

in the years since then, all

10:35

of the trials, you know, with the SGLT

10:37

two inhibitors, the GLP one agonists,

10:40

all of the data that came out was

10:42

a result of Seeing

10:45

a signal with Rosa Glitazone

10:47

acting on the information, being

10:50

decisive about writing up the manuscript

10:53

and publishing it and standing

10:55

behind the findings. And you

10:57

know, so there were two pretty large,

11:00

very large, I mean, headline

11:02

news, drug safety issues.

11:04

You know, I got accused by some people

11:06

who, for various reasons, wanted

11:09

to believe it, that I was somehow. An

11:12

anti-drug industry, which of course is not

11:15

the case. We need a great drug

11:17

industry to develop new therapies

11:19

for patients, but we have to

11:21

be prepared to tell people

11:23

what works, what doesn't

11:25

work, and what's harmful, and

11:28

to provide equal weight. To

11:30

the findings, regardless

11:32

of which direction they

11:34

go. And, and Dr. Nissen, I'll just

11:36

jump in there because I remember

11:38

hearing the story as a first year fellow when we

11:40

were rounding in the unit, and I,

11:43

I couldn't believe it. And I wanted to highlight for

11:45

our listeners that. You know, indirectly

11:47

you probably had a lot of pharmaceutical mafia

11:50

people come after you, but at the same

11:52

time, the this, this

11:54

sort of action is kind of why we have

11:56

SGLT two s and GLP one s

11:58

because of that push for having cardiovascular

12:01

outcomes. So, I mean, you're

12:03

saying the story, but I think it's even bigger

12:06

than, than this because this has shaped some

12:08

of our newest drugs that we use in all of these

12:10

patients.

12:11

No one would be able to use

12:13

these drugs if we hadn't required the trials

12:15

because you know, the pharmacy benefit

12:18

managers would say, well, why should we pay for a drug

12:20

when all it does is lower blood sugar, the

12:22

same way of sulfonylurea or any

12:24

other drug lowers blood sugar. So

12:27

it turned out it actually helped the industry,

12:29

but it helped patients. That's what really counts.

12:32

And you know, I proudly

12:34

stood behind the data. It was

12:37

a very difficult time

12:39

because you know, I can tell

12:41

you that if you do take on a

12:43

multi-billion dollar industry,

12:46

they're gonna come after you and you better have

12:49

thick skin. And you better be willing

12:51

to stand your ground. But I'm pleased

12:53

with how it all worked out. And I do think

12:56

you're right. There have a number of people

12:58

have written about what happened, and

13:00

in fact, there was 172 page

13:03

report from the US Senate after

13:05

they had held a bunch of hearings that

13:08

goes into all of the gory details,

13:10

one of which was unbelievable

13:14

that when we submitted the manuscript

13:16

within 24 hours, one

13:18

of the reviewers. Who had a financial

13:21

relationship with GlaxoSmith Klein

13:25

gave him a copy of the manuscript

13:27

while it was in review, which is wow considered

13:30

highly unethical. And

13:32

as a result the

13:35

company knew it was coming. And

13:37

they plotted their strategy

13:39

on how to character assassinate

13:42

The two authors myself and, and Ms.

13:44

Wolski, and, you know, this

13:46

all came out in the Senate report that

13:48

the, the, the senators

13:51

discovered with subpoenas the

13:54

actual facts that had gone

13:56

from the, from the reviewer to

13:59

the company. That had given

14:01

them a copy within hours

14:04

of its submission of the manuscript

14:06

I'd submitted to the New England Journal.

14:10

That is a, that's a tremendous story.

14:13

We, we are familiar with it, but yeah.

14:15

But it's great to hear, it's great to

14:17

hear her firsthand accounting of it though. That's

14:20

tremendous. So, so Steve, before we spend

14:22

the last 10 or 15 minutes talking about some of the

14:24

newer. Trials. Yeah. I

14:27

did want to ask you, you've spent, you have so

14:29

much experience conducting trials that

14:31

have been so seminal, and of course you

14:33

review trials as well for some of

14:35

our young, early practi, early career

14:37

practitioners, our fellows in training our nurse

14:40

practitioners. as you know, the, the

14:42

medical literature has just exploded and specifically

14:45

the cardiovascular literature. So

14:47

when you, when you approach a trial

14:49

as a reader, as a clinician in your clinician

14:51

hat, And you're trying to determine,

14:53

the relevance and how it may apply to your patients.

14:56

Are there a few things you focus on

14:59

to help kind of, clear the wheat from the

15:01

shaft and figure out which, which

15:03

studies really are gonna have impact

15:05

and, and, and contain actionable

15:07

information? How do you approach, you know, well,

15:10

that's

15:10

a great question. You, you certainly

15:12

have to dive deep and

15:17

I find that some

15:19

of the best information. Is

15:22

actually in the supplement that almost

15:24

nobody else reads, and I'll give

15:26

you an example of that. You

15:28

know, the Reduce It manuscript

15:30

came out with a Casa Pyl, otherwise

15:32

known as vascepa, and it

15:35

just seemed too good to be true. And

15:37

so I'm looking at the supplement

15:40

and and buried on the

15:42

last page of the supplement or nearly

15:44

the last page, I

15:46

find a single line that

15:49

shows what happened to

15:51

high sensitivity C reactive protein

15:53

in the two treatment arms. And it

15:56

turns out that in the control

15:58

arm, which was a mineral oil

16:00

placebo, there was a 30

16:03

plus percent increase.

16:06

C-reactive protein unheard

16:09

of. And what

16:11

that led to was a series of investigations,

16:14

and I think there are a lot of people who now agree with

16:17

me that basically it's

16:19

a false positive study that

16:21

instead of using a neutral placebo,

16:24

the trial used a placebo

16:26

that was toxic. And

16:28

so the apparent benefits of

16:30

ACO ethyl were actually

16:33

due to the toxicity of the control

16:35

of the placebo and not to the benefits.

16:38

If I hadn't looked deeply

16:41

into that supplement, And

16:43

everybody else missed it. Nobody. Nobody

16:45

really saw it. And then

16:47

later on, Paul Ricker did

16:49

an analysis of blood samples

16:51

from the trial. And every

16:54

inflammatory marker you can

16:56

imagine went. Incredibly

16:59

bonkers up with

17:02

the mineral oil treatment group.

17:04

And so it's a classic example of a drug

17:07

that got a, got a label from the F D

17:09

A. It's widely used. It

17:11

is not, it does not produce

17:14

favorable effects. It's a false positive

17:16

study. Yeah,

17:19

and I think Dr. Nissen, that that point of

17:21

diving into the. Like the details,

17:23

the supplemental indices,

17:25

it's, I guess the challenge is there's

17:28

so many of these clinical trials that come

17:30

out and in general, cardiology,

17:32

you are spanning prevention, imaging,

17:35

when to intervene on patients. How

17:37

do you, is there a guide you use,

17:39

like do you follow certain journals specifically? How,

17:42

what would be your words of advice for, for the general

17:44

practitioner to make sure they're staying up

17:46

to date? Well, I think first of all, the

17:48

tier one journals, which are, you know, jama,

17:51

new England Journal and the Lancet a

17:54

lot of the most weighty research

17:56

appear, not all of it, but a lot of very most

17:58

important research appears in those three journals.

18:01

And I try to look at them and

18:03

I think there is time for most cardiovascular

18:06

practitioners to, to read.

18:09

The cardiovascular studies that

18:12

are published in those

18:14

top three journals, I mean, that's

18:16

just not a big lift.

18:19

And, you know, look, I work very hard,

18:22

you know, I'm one of the oldest people in our department,

18:24

but I'm the first one there in the morning. I

18:26

get there at four 30 or five in the morning every

18:28

day, off and on weekends.

18:31

I spend the time that I have as

18:33

productively as I can, and I do read

18:35

the literature carefully so

18:37

I can stay informed, and it helps

18:39

you pose the questions.

18:42

That you wanna ask? You know

18:44

it's kind of interesting because

18:47

there are always people that are

18:49

gonna push back. I was just remembering

18:51

again about the whole glitazone controversy.

18:55

And when I propose requiring

18:58

outcome trials for diabetes drugs, many

19:01

people in the diabetes community looked

19:04

me in the eye and they said, if you do

19:06

this nien, we will never have

19:09

another diabetes drug. Because

19:11

no company's gonna make the investment in

19:13

doing the outcome trials. Well, you

19:16

can see what's happened since then up

19:18

just a proliferation of

19:21

very, very good trials.

19:23

Yeah, I definitely agree that that was a courageous

19:26

move. And, and kind of before we jump

19:28

into now, the, the current lipid

19:30

trials, including clear Yeah, I, I

19:33

did have a question. Sometimes we have patients

19:35

listen and. I

19:37

think it's, it's sometimes a an

19:39

art to explain to them the importance

19:42

of enrolling in clinical trials with the chance

19:44

that they get a placebo. Obviously

19:47

patients want to be treated. How,

19:50

how have you kind of navigated that as somebody who's

19:52

run several clinical

19:55

trials? Yeah, yeah. Even for example,

19:57

in the mava campton trials Yeah. That you've been

19:59

involved in. How do you, how do you kind of approach patients

20:01

in that way?

20:02

Well, first of all, patients who volunteer

20:05

for clinical trials, it is a noble

20:07

endeavor and they do so for very good reasons.

20:10

They do so they will say to us, we

20:12

know this may not help me, but

20:15

if it helps somebody else, I think

20:17

it's worth it. The other thing

20:19

that is really amazing, there have been multiple

20:21

studies published that people

20:24

that are in the placebo harm.

20:27

Of randomized trials do much,

20:29

much better than the general population.

20:32

Why is that? It's because

20:34

they get very good medical care. They

20:37

get managed to, you know, with state-of-the-art

20:39

control of their risk factors. They're

20:42

seeing people frequently,

20:44

you know, the nurse coordinator and or the,

20:47

the principal investigator at the local

20:49

site. And so they do better.

20:52

And so being, just being in a clinical trial

20:54

gives you an advantage over

20:56

people who are not in a clinical trial.

20:59

And that's the truth. There's lots of studies

21:01

that show that.

21:04

Yeah. And I can imagine once,

21:06

once patients wrap their head around that, but

21:08

also if they have the courage to continue to,

21:11

to be somewhat altruistic, it really shapes

21:13

the field because as much as the, the

21:15

clinical trial is running the trial, it's

21:17

the patients who are involved who push it forward as

21:19

well. You bet. So,

21:22

Dr. Ni, can you just tell us because

21:25

you noted this, Difference

21:27

in the omega-3 trials. Can

21:31

you just tell us how from the Cleveland Clinic

21:33

group, there was a, a, not a rival

21:35

trial, but a, it was sort of proof of concept

21:37

trial that was conducted as well?

21:40

Yeah. How did you kind of

21:41

start that? Well that was started

21:43

actually our trial was with a different

21:46

product. Very similar in many ways,

21:48

to a Casa Pyl or

21:50

vascepa. It was just a little different

21:52

formulation and we ran

21:55

the trial. It was, it was actually larger

21:57

than reduce it and

22:00

it showed no

22:02

benefit. There was just

22:05

nothing and. We

22:08

said to ourselves, I, you know, this was,

22:10

this was finished just a few months

22:12

after reduce it. We said, how

22:14

can one fish oil

22:17

that does low risk triglycerides

22:19

a little bit, does a few other things, show

22:22

a 25% reduction in morbidity,

22:24

mortality, and another product

22:27

that is almost the same

22:30

chemically show

22:33

zero benefit. Something

22:35

had to be wrong there. And

22:38

the, the, of course, the, I,

22:40

I had a very good idea what it was.

22:42

And it was the, the problem

22:45

with the placebo we

22:47

used and we knew, by the way,

22:49

that mineral oil was probably toxic

22:52

when we designed the strength

22:54

trial. We did

22:56

was, again, similar in size, you know,

22:58

12,000 patients, I mean bigger in size,

23:00

12,000 patients. We

23:02

chose corn oil as

23:04

the placebo because we thought corn oil

23:06

was about as neutral as you can get. We

23:08

thought olive oil was beneficial. We

23:11

knew that there were issues around mineral oil,

23:14

so we chose something deliberately.

23:17

That was neutral and

23:19

there was no difference between corn oil

23:22

and the same four gram

23:24

dose that was used and reduce

23:26

it with just a little bit different

23:29

product. And so at the

23:31

end of the day, it just didn't seem

23:33

possible that these two trials

23:35

could have completely opposite

23:37

results. Something else

23:39

had to explain the differences.

23:44

Yeah. Thanks Steve. That that makes sense

23:47

to set the stage for our last

23:50

15 or 20 minute discussion about, you

23:52

know, clear and. Other agents.

23:54

I'm, I'm really fascinated by, you know, the

23:56

concept of statin intolerance. I

23:58

was reviewing some of your previous articles about

24:01

that in the last several years, and

24:03

I, I think you have a very interesting definition

24:06

of it. And one thing you raised

24:08

in one of your, your editorials a few years

24:10

back was a concept that perhaps with

24:12

statin trials, you know, the fact that patients

24:15

have to be recruited into these studies, that somehow

24:18

we're selecting a group of patients

24:20

who are less prone. To the side

24:22

effects because, you know, just like you, I'm

24:24

a clinic clinician who's in

24:26

clinic almost every day taking care of patients.

24:29

And you know, the concept of statin intolerance

24:32

comes up almost daily, multiple times

24:34

with our patients. And of course, when

24:36

you look at the literature of, of the incidents, there's

24:38

such a dichotomy between what we see in

24:41

the real world. And it looked like in

24:43

some of your editorials, you addressed that. So

24:46

I was wondering if you could just review how, how you put

24:48

that in perspective with some

24:50

of your

24:50

patients. Well, first of

24:52

all, it is a very controversial topic.

24:55

You know, there is a group in Europe, in, in the UK

24:57

that thinks it doesn't exist. There

24:59

are other people that Build

25:01

their entire careers on

25:04

the treatment of patients with,

25:06

with statin intolerance. You know,

25:09

my, I have a very pragmatic view

25:11

of this. There's two things I really

25:13

think people should know. One is

25:16

that most of the clinical trials that

25:18

have been conducted have

25:20

a run-in period where you get

25:23

the drug. And, you

25:25

know, if you have an

25:27

inability to tolerate the drug, then

25:30

you're not randomized. So you have this,

25:32

this run-in, in advance

25:35

of actually conducting the trial.

25:37

And so you remove from the study

25:40

all the people that are statin

25:42

intolerant and the other

25:44

Quest Other issue is really

25:46

a very practical one. If

25:48

a patient comes in your clinic Kenny

25:51

and says, You know, I

25:54

have tried the statins, I've tried

25:56

multiple statins. I can't

25:58

tolerate the statins and

26:01

I won't take a statin. And they

26:03

have a very high L D L in their, you

26:05

know, they've had a previous event. What are you

26:07

gonna do? You, you can't

26:09

force a patient, take a drug they don't wanna

26:11

take. And so we have to have practical

26:14

alternatives, even if

26:16

you think that it's in their head from

26:19

that. For them it's real.

26:22

Absolutely. Well, thanks

26:25

to you and other trialists. Fortunately we

26:27

we're increasing our armamentarium now.

26:29

Yeah. So that so that we do have

26:32

many more options.

26:34

we're gonna focus on the newest on

26:37

his newest trial, the clear trial. I'm gonna

26:39

just give a brief summary so that

26:41

Dr. Nissen doesn't have to start from, from ground

26:43

zero here. The clear trial published in New

26:45

England Journal was randomized

26:47

about 13,000 patients. Who

26:49

are at high risk for atherosclerotic

26:51

cardiovascular disease and who are unable

26:53

to take more than a low dose statin

26:56

to either the placebo arm or

26:59

beo acid. And that's the drug that

27:01

is being tested. And

27:04

so they randomized 13,000 patients. And

27:06

their primary outcome was a, a composite,

27:08

the standard, major adverse cardiovascular event,

27:11

composite of death from CV causes

27:14

non-fatal mi, non-fatal stroke and

27:16

need for coronary revascularization, and

27:18

they found a a, a significant

27:20

reduction. In Mace.

27:24

And, and kind of the, the main things that we

27:26

thought that this was so applicable clinically was

27:28

because it, it adds to the armamentarium

27:30

for our primary prevention patients who are

27:32

at high risk and don't have options

27:35

because of intolerance. And so

27:37

from there, just with that background, Dr.

27:39

Nissen I kind of just wanted

27:41

to ask you from the, from the get-go, what did you

27:43

foresee when you were initially starting

27:46

the design of the trial? Well,

27:47

we knew that beo

27:49

acid is a pro-drug. It's

27:52

not active in peripheral tissues. It

27:54

gets taken up by the liver where it

27:56

gets converted to its active

27:58

form. And so if it's not

28:00

active in peripheral tissues, it

28:02

can't cause the kno myalgias

28:04

that many patients complain about when

28:07

they take statins. And we had

28:09

pretty good evidence from smaller trials

28:12

that it didn't seem to produce the kind

28:14

of musculoskeletal problems and statins.

28:16

Produce. So it made sense

28:19

then to study this drug

28:21

in statin intolerant patients. Now,

28:23

just wanna make sure you understand that about

28:26

80% of the patients were on no statin.

28:28

They couldn't tolerate any. And

28:30

about you know, 20% or so,

28:33

were on less than the lowest approved

28:35

dose of a statin, like on

28:38

10 milligrams of atorvastatin twice

28:40

a week. That sort of thing. So

28:43

these are really people that are statin

28:45

intolerant and we made 'em sign a statement

28:48

that they would not take a statin

28:51

even though they knew statins

28:53

could reduce their risk of heart attack, stroke,

28:56

or death. So we did

28:58

this in an ethical way. I thought it was very important

29:00

to do that. And we

29:02

were able to find at 1,250

29:05

sites in. You

29:07

know, something like 32

29:10

countries the patients

29:12

were enrolled and, you know,

29:14

we've went on for a number of years.

29:16

We followed them for about 41

29:19

months. And of course,

29:21

there's nothing in the world quite

29:23

like unblinding, a trial you've worked

29:25

on for many years and finding out

29:27

whether it worked or it didn't work.

29:33

And I, I know that the trial did include almost

29:35

50% women, which is nice

29:37

to see as well. Yeah. So

29:40

I was curious though, you do have kind of a mix of

29:42

primary and secondary prevention patients in

29:45

the study. Have you analyzed

29:48

any differential effect in, in those two groups,

29:50

those with known c a d and those with, with

29:52

risk factors

29:54

only? I thought you'd never

29:56

ask. So you

29:58

have to come to the a d A meeting.

30:00

It's on the program where we

30:02

are going to present detailed results

30:05

in the 30% of patients, 4,200

30:09

patients. They were primary

30:11

prevention. They had high risk factors, but they'd

30:13

never had an event. And

30:15

if you looked really carefully at

30:18

the supplement, you will notice

30:20

that there appeared to be a more favorable

30:23

effect in the patients that

30:25

were in the primary prevention strata

30:28

than those that were in the secondary prevention.

30:30

We're gonna tell you a lot more about that.

30:33

I'm gonna present it at

30:35

ada. And it will be simultaneously

30:38

published in a major

30:41

journal.

30:43

And I think that's, that's good. That's the hook right

30:45

there, Dr. Nissen. And also another plug

30:47

for you for us to take

30:49

a look at the, the depths of these articles,

30:51

including the supplementary indices. Yeah.

30:53

When you, when you talk about bedo

30:56

acid, a lot of, a lot of what people say about

30:58

statins is this pluripotent effect including

31:01

on anti-inflammation.

31:04

And c r p has been used as a, as a marker

31:06

for this. Can you just help us as, as far as

31:08

statins, we kind of understand

31:10

some of that. But as far as beo acid,

31:12

what's its relationship to inflammation that you found

31:15

in the trial?

31:15

Well, keep in mind that beo acid works

31:18

in the same pathway as statins, but upstream,

31:21

and it has quite intense

31:24

anti-inflammatory effects. We

31:26

got about the same amount of

31:28

reduction in high sensitivity C R

31:30

P. As we got reduction

31:33

in L D L cholesterol, so it

31:35

has two potential ways

31:37

to benefit patients, both as an anti-inflammatory.

31:40

And we now know that anti-inflammatory

31:43

drugs like Colchicine or Kinumab

31:46

do have cardiovascular benefits. And

31:48

of course, we've known for a long time that L

31:51

D R reduction has benefits. Baic

31:53

acid does both. What we didn't

31:56

study. And I wish we could have,

31:58

but we couldn't for a lot of regulatory

32:00

reasons, is the drug

32:02

is available, Beto acid, both

32:04

as monotherapy and

32:07

in combination with ezetimibe. The

32:09

combination with Ezetimibe produces

32:12

a 35 to 40%

32:14

L D L reduction. It's about

32:16

the same as 40 milligrams of simvastatin,

32:19

and so we can get a pretty

32:21

robust L D L reduction with

32:24

that combination without

32:26

having to give a statin to

32:29

those patients that simply won't or

32:31

can't take a statin.

32:34

Yeah. So I think that that's awesome that that offers

32:36

another option. Yeah. Now to,

32:39

to speak to this point though what

32:41

has been brought up is something, something about cholelithiasis,

32:43

something about gout. Yeah. As far as the,

32:46

the true side effects, because we know what statins

32:48

cause. How would you frame that

32:50

from what you've seen in the, in the patient

32:53

outcomes and, and maybe just how you would

32:55

translate that clinically. Do we use it in patients with

32:57

gout already or use it with caution, et

32:59

cetera? Yeah,

33:00

I would be very careful and probably

33:02

I would not use it unless I really

33:05

felt I had no other option in patients

33:08

with a strong history of gout.

33:10

Unless, of course they had

33:12

been on a uric

33:14

acid lowering agent for some time

33:17

and had very good, you know, low uric

33:19

acid levels. Those people I would be okay

33:21

with. But, you know, I would worry about

33:24

triggering gout. Now look, if

33:26

you, if you wanna trade off gout,

33:28

Versus a heart attack, I'd kind of take a gout

33:30

attack any day of the week. Having

33:32

said that, you know, we don't want to be cavalier

33:35

about these things. We had not

33:37

previously seen csis,

33:40

but there was an excess, about 1%

33:42

excess of colonese.

33:45

In the Baic acid group, you

33:47

know, again, it was generally not

33:50

something that led to surgery

33:52

or sepsis or anything like

33:54

that, but it was an excess,

33:57

and people need to be aware of that. Look,

34:00

let's be very clear, there is no

34:02

such thing as a free lunch. Every drug we

34:04

give patients has pros

34:07

and cons. It's important, I think,

34:09

for clinicians to know the upside.

34:12

To know the downside and to

34:14

make an educated decision

34:16

with the patient at the table,

34:19

so-called shared decision making. Lay

34:22

out the risks, lay out the benefits,

34:24

make a decision together on what direction

34:26

to go.

34:29

Steve I was also there in the audience at

34:31

a ACC C when you presented this to

34:33

much excitement. I, I

34:36

know there were, there was one question asked

34:38

at that time about the fact that, you know, you

34:40

had a. Combined out outcome,

34:43

not a mortality benefit

34:45

directly. Yeah. And yeah, and you know, I'm

34:47

wondering do you think that's relevant or do you

34:49

think the fact that most likely this is gonna

34:51

be used in combination with Ezetimibe

34:53

and further LDL lowering, and of course

34:55

Ezetimibe has pretty good evidence base

34:57

behind it now, do you think that makes the mortality

34:59

issue a little less relevant?

35:01

Yeah. Okay. It's not irrelevant. It's highly

35:04

relevant, but here's the

35:06

issue. Both

35:08

large PCSK nine inhibitor

35:11

trials, one of which was 27,000

35:13

patients had absolutely

35:16

no benefit on mortality with

35:18

a 50% L D R reduction.

35:21

Almost all the modern trials in

35:23

secondary prevention patients have not

35:25

shown a reduction in mortality. We

35:28

didn't see it for Alloc,

35:30

for Evolocumab. You know, I

35:33

could go on and on and on about

35:35

the trials that did not show a death

35:37

benefit. Why is that? It's

35:40

because of everyone listening

35:42

to this podcast. We've

35:45

become very good at treating

35:47

people with acute mis. People

35:50

don't die of acute MI very

35:52

often anymore. They may die. 7,

35:56

8, 10 years down the road.

35:58

Or they may ultimately later on develop

36:00

heart failure, but they don't die

36:03

in the short run. And so

36:05

I don't think we're gonna see lipid

36:07

lowering therapy even with these

36:09

very powerful L D

36:11

L lowering drugs. Reduce mortality. We

36:14

didn't see with baic acid, we

36:16

didn't see it with PCSK nine inhibitors.

36:19

It's just too much of a reach

36:21

in the contemporary era.

36:24

Yeah, and I think that does make complete sense,

36:26

so thanks for clarifying. So

36:29

as we kind of put this study

36:31

with Bedo acid in perspective with

36:34

so many other, you know, existing

36:36

or agents

36:38

that are on the way, I'm

36:41

just curious to finish up in the last five minutes or

36:43

so how you approach,

36:45

you know, all of the statin alternatives now

36:47

in your mind. Obviously we know

36:49

that for primary, excuse me, for secondary

36:51

prevention patients, we're always gonna start with a

36:54

high dose statin. And we know, we know we

36:56

have very good data about target LDLs.

36:59

But how would you rank this drug

37:02

with say, PCSK nine inhibitors, which you

37:04

just mentioned, as well as Zein

37:07

and some of the others as you approach

37:09

a patient who say statin intolerant.

37:11

And then as a follow up, a patient who doesn't

37:13

get to go. On the maximum

37:16

statin dose they can tolerate.

37:18

Well, Kenny, you said something interesting,

37:20

which of course, which I agree with, which is

37:23

that we have good idea of what target staff

37:25

for L D L. Unfortunately, we haven't

37:27

been able to convince our guideline writers

37:29

that that's the, that that's the case. But

37:32

having said all of that I

37:34

do believe that lower is better. And

37:37

the higher the risk the patient, the lower you wanna

37:39

go. Statins

37:42

are the first line drug. They're the second

37:44

line drug, and they're the third line drug. And

37:46

we try, try and try

37:48

again. If

37:51

we get 'em on, get patients on a statin

37:53

and their l d L is still above where

37:55

we want it. The

37:57

natural thing to do is to add ezetimibe

38:00

because it's generic, it's inexpensive,

38:02

it's very well tolerated, very safe.

38:05

There will be people that will not

38:08

get there. With adding ezetimibe,

38:11

and they will need a PCSK nine inhibitor.

38:14

And that includes now lyran,

38:17

which is a, you know, very attractive

38:19

drug because it's so long acting

38:22

that you only have to give it twice a year

38:24

if people cannot tolerate

38:27

evidence-based. Doses

38:30

of statins, well then

38:32

we have alternatives like beo acid

38:34

or beo acid with ezetimibe,

38:37

and if they need a lot of L D L

38:39

reduction, then even beo

38:41

acid with ezetimibe may not be enough,

38:44

and we may need to go to a PCSK nine

38:46

inhibitor. Here's what's really fantastic.

38:50

We have a lot of tools in the tool

38:52

chest, and we can pick them

38:54

based upon the pharmacoeconomics

38:57

patient need. What patients

38:59

tolerate, what our goals are,

39:02

but I hope everybody will, will remember

39:04

and please share with me this view

39:07

that the higher the risk, the

39:09

lower, we wanna take. The L D L. The

39:11

evidence is compelling

39:14

that lower LDLs lead to

39:16

reduced rates of event and

39:18

re reduced rates of disease progression.

39:22

Dr. Nien, that's you said a couple

39:24

key things there that we'll highlight and, and

39:26

I think first, second, third line is statins.

39:29

And, and like you just said, even just this past week,

39:31

I've gotten asked by some of my interns

39:33

colleagues is, is there ever

39:36

a too low in, in some high risk

39:38

primary prevention and secondary prevention? And I think

39:40

you. You clearly state that and we'll

39:42

have links to some of these landmark trials,

39:44

including your initial New England

39:47

Journal piece about Rozi, Rosie Glitazone.

39:49

Yeah. To to end this

39:51

is more on like a philosophical topic.

39:54

Yeah. Dr. Nisson, I've had the pleasure of working with you for

39:56

now, three and a half, four years, rounding in the unit with

39:58

you for several hours each day, and, and

40:01

I've, I've kind of noticed and, and

40:03

heard some of your stories, but. You

40:05

know, after, after kind of seeing through

40:07

different eras in cardiovascular medicine, being

40:09

a, a major player in that, you

40:12

know, we have a lot of people who are listening who are

40:14

early career and some who are

40:16

really motivated mid-career and late

40:18

career docs. What motivation

40:20

would you give them? What, what words of advice would you give

40:23

them on how to stay on top of things?

40:25

How to keep interested. And,

40:27

and how to push your career forward. How,

40:29

what would you give like a, a last parting

40:32

statement? Well,

40:33

I could tell you is there's no, there's no

40:35

easy route, you know,

40:38

and get to work early, you know,

40:40

keep your, your eye on the literature

40:44

you know, dream big. Never

40:48

believe that you can't accomplish

40:50

something. I'm gonna tell

40:52

you one final story. There

40:54

was a, a guy who at the time

40:57

was a fellow who got the idea

40:59

that may, he saw me giving nitropress

41:01

eye to patients with aortic stenosis,

41:04

and he said, shouldn't we study that in an R

41:06

C T? So he designed a 25

41:09

patient, R C t. That

41:11

we did in the C C U showed

41:14

that Nitro Proxide made people with critical

41:16

as better, and he got it published

41:19

as a fellow in the New England Journal

41:21

of Medicine. Dream Big.

41:25

That's fitting Steve. Yeah, that

41:27

was my only question is does Ben really show

41:30

up for rounds in the C C U at four 30 when you

41:32

get there? Cuz I have a hard time

41:33

believing that. Well, what happens of course, is the

41:35

fellows know what time I get up,

41:38

so they always make sure they get there a little

41:40

before I

41:40

do. I'll tell you those weeks.

41:43

Breakfast is just earlier. That's it? Yeah.

41:46

I start rounds at seven only because

41:48

the residents would be furious. It would be

41:51

if I made 'em round at six, I just assume

41:53

round at 6:00 AM

41:55

That's so funny. Hey, Dr. Nissen thanks

41:57

so much.

41:58

Thank you for joining today's podcast.

42:01

For more information about the speakers or

42:03

the topics, please go to Ohio

42:05

acc.org,