2:00

In the coming weeks this winter, there will be plenty

2:02

of AHA studies to discuss. Today

2:05

I'm going to do the big ones. So

2:08

first topic is semiglutide and

2:10

the select trial. The glucagon-like

2:13

peptide agonist, semiglutide, has

2:15

been shown previously to reduce outcomes

2:17

in patients with diabetes.

2:20

It reduces weight in patients with obesity.

2:23

The placebo-controlled select trial tested

2:25

it as a disease-modifying agent in

2:27

patients with obesity and established atherosclerotic

2:30

cardiovascular disease and the drug

2:33

worked. Clearly it worked. Select 17,000

2:37

patients. The

2:39

most common qualifying vascular disease

2:41

was post-MI, demean age, 62 years

2:43

old, mostly male.

2:46

In all patients who are already on baseline

2:49

guideline-directed medical therapy, so any gains

2:51

from semiglutide are on top of

2:54

modern medical therapy. The

2:57

mean BMI in patients was 33. The

2:59

trial did include patients with overweight

3:02

as well as obesity. Primary

3:04

endpoint was a MACE endpoint, cardiovascular

3:07

death, MI, stroke and the trial

3:09

was positive. In the

3:11

semiglutide arm, 6.5% of patients

3:14

experienced the first primary outcome event

3:16

versus 8.0%. This 1.5%

3:21

absolute risk reduction translated to a 20%

3:24

relative risk reduction and

3:26

this was a highly statistically significant

3:29

result. Now, there were other notable

3:31

and positive findings that were induced in

3:33

the semiglutide group. Patients

3:36

lost about 8.5% more of their body weight

3:39

than in the placebo arm. The

3:41

Kaplan-Meier curves for the primary endpoint

3:43

began to separate early and

3:45

this is well before weight loss took effect and

3:47

that certainly suggests. Other

3:49

ways that the drug may confer its benefit,

3:53

each component of the primary endpoint was lower

3:55

including cardiovascular death, overall death

3:57

was nearly 1% lower. And

4:00

these positive findings like I mentioned occurred

4:03

in the setting of already robust baseline

4:05

care including statins and antiplalae agents

4:08

in approximately 90% of patients. The

4:12

drug also reduced the

4:14

onset of prediabetes by 75% and

4:17

also levels of C-reactive protein and

4:19

systolic blood pressure were lowered.

4:22

Now there were adverse events, adverse

4:24

events that led to stopping the drug occurred

4:27

in 16.6% of those taking the semiglutide versus 8.2% on the placebo.

4:34

So my comments, I don't know how else to feel

4:36

about this other than it's a positive

4:38

trial and it's a big change. The

4:41

degree of relative and absolute risk

4:43

reductions are similar to statins. Only

4:46

patients who are overweight and obese also

4:48

get the benefit of weight loss and likely feel

4:50

better with semiglutide. So

4:53

it's a cardiovascular outcome

4:55

reducing drug that also helps

4:58

patients feel better and lose weight. Now

5:01

since I'm super positive on select maybe

5:03

you'd have a counter. Maybe you

5:05

might say we shouldn't do this indication because

5:08

it's only one trial. For new indications we

5:10

should have two trials and

5:12

I would normally agree but I'd also say that

5:15

it's not like GLP1 agonist

5:17

don't have priors on being cardiovascular

5:20

event reducing drugs. So

5:22

I would say that it's a 16.6 trial that showed that

5:24

semiglutide reduced cardiovascular outcomes

5:26

in patients with diabetes. Plus

5:29

I would add that it's quite plausible right

5:31

that inducing nearly a 10% weight loss is

5:35

going to improve things like blood pressure,

5:37

glucose, inflammation and

5:39

all of these factors likely lead

5:41

to lower rates of recurrent MI or

5:44

strokes. I think that select

5:46

is going to change practice. For

5:49

patients with established vascular disease

5:51

who are overweight or obese semiglutide

5:53

is a disease modifying drug and

5:56

we will likely be using it. Now

5:58

the other thing. that select may

6:01

change, I hope, is the

6:03

framing of obesity. Now,

6:05

since we have a drug that induces weight

6:07

loss and improves outcomes, the

6:10

next step in that logic would

6:12

be that obesity is not healthy. Right

6:15

now, one of the headwinds of treating obesity

6:18

is the tension that's created by this cultural

6:20

sense that all body types are okay. I

6:23

hope that select and the GLP-1 agonist

6:26

in general change norms around obesity

6:29

to make it more thought of as a serious

6:32

medical condition that requires intervention.

6:36

Now, another discussion point at AHA was that the Kaplan-Meier

6:38

curve separated early and that

6:40

implicated mechanisms of benefit

6:43

beyond weight loss. And I think that

6:45

is right too. Now, I don't know what

6:47

it is exactly. Maybe it's just simply

6:49

eating less. But the thing

6:52

about trials that make them so important is

6:54

that the why answer is less important.

6:57

Trials show us whether things work or they do

6:59

not. And semiglutide sure looks like it works.

7:03

Now, finally, there is the cost. I

7:06

don't have the answer here. But we'll

7:08

have to find a way to get a disease-modifying

7:10

drug to people in an equitable fashion.

7:13

And I know health economics isn't

7:16

simple, but my mind is simple. So,

7:18

mandrola thinking holds that if

7:21

we stopped burning money on low-value care, wink,

7:25

left atrial appendage occlusion, excess

7:29

AF ablation, coronary calcium screening, we'd

7:32

have more for proven therapies that

7:35

are proven in randomized controlled trials. I

7:38

would say congratulations to the researchers

7:40

and get this to Novo Nordisk, the makers of the

7:42

drug. I think

7:44

here is an example where industry

7:47

and innovation has improved societal health.

7:52

Alright, second topic is ORBETA 2. In 2017, Imperial

7:54

College investigators nearly

7:56

killed... interventional

8:00

cardiology with their orbita 1 trial.

8:04

At AHA, they presented orbita 2

8:06

and interventional cardiology

8:09

which was nearly lost is now found

8:11

and saved, thank goodness. Before

8:14

I say anything else about the trial, I want to point

8:17

out something that I've been thinking about and

8:19

how special Imperial

8:21

College must be, right? Darryl Francis,

8:24

Rasha Al-Lao Mi, must be much

8:27

more than incredibly smart scientists. They

8:29

seem to be really wonderful leaders

8:31

as well because the Imperial

8:33

College team not only puts out unique research,

8:36

think also the Samson trial with statins,

8:39

but they also seem like a big

8:41

happy family when you meet them. Now

8:43

another clue on leadership and I want

8:45

you to watch for this in future trials. Back

8:49

in 2017, Darryl Francis had Rasha

8:53

Al-Lao Mi present and take first authorship

8:55

of orbita. That's

8:56

nice. In 2023, Rasha Al-Lao Mi

8:59

had Christopher

9:01

Rajkumar present orbita 2

9:03

and take first authorship.

9:06

As a person who participated

9:08

in team sports all his life,

9:11

I really appreciate this sort of leadership.

9:15

Okay, let's move on. As many of you know, orbita 1

9:18

really shocked the interventional community when

9:20

it studied a placebo PCI. We

9:22

used to call it a sham, but we don't anymore because

9:25

sham doesn't really fit against

9:27

a real PCI. So placebo PCI,

9:30

real PCI. Now just pause for a second

9:33

and picture a patient with an angiogram,

9:35

any angina and a 90% proximal

9:38

stenosis somewhere. Imagine

9:40

the boldness to put a pressure wire across it

9:43

and leave it unfixed and

9:45

in orbita 1 when patients with these

9:47

single vessel lesions were first maximized

9:50

on anti-anginal therapy. Fixing

9:52

the lesion may no significant difference on exercise

9:55

time or angina scores versus

9:57

placebo PCI or

9:59

Orbita showed that PCI as an

10:02

add-on in this setting did little

10:04

more than placebo. But

10:06

Orbita 2 was different and asked and studied

10:09

a different question. So

10:11

patients with single or multivessel

10:13

disease and chronic stable angina were

10:16

recruited. They then had their anginal

10:19

medicines stopped two weeks before

10:21

the procedure. Then they

10:23

went to the cath lab and were randomized

10:26

to either a real PCI or

10:28

a placebo procedure. And their

10:30

blinding procedures were extensive

10:32

which is of course is critical. Patients

10:35

and physicians can't know which

10:37

group patients were in. Orbita 2

10:40

authors also designed an app wherein

10:43

patients would report daily anginal episodes

10:45

and a number of anti-anginal drugs. This

10:48

allowed the investigators to create an ordinal

10:50

score which they used for their primary end

10:53

point. They also of course

10:55

measured treadmill time and other angina

10:58

questionnaires. With this new

11:00

design, one that isolates

11:02

the effect of PCI alone, not

11:04

as an add-on procedure, PCI

11:07

did work. It worked to improve the angina

11:09

symptom score. The odds ratio

11:11

was 2.2 for a better angina

11:14

score which was highly positive and significant.

11:17

And a frequency was also 3.4 times

11:20

less often in the PCI

11:22

arm. PCI also improved the Canadian

11:25

cardiovascular class angina scales.

11:28

And treadmill walk time was now

11:30

a statistically significant 59 seconds

11:33

better than the 16 seconds

11:36

in orbita 1. So a very

11:38

positive trial for PCI. Some

11:42

may wonder about the ethics of stopping

11:44

pills two weeks before randomization.

11:47

But I would say that it is totally ethical

11:49

because recall that in patients with

11:51

chronic stable angina, angina

11:53

medicines are not disease modifiers.

11:56

Their like acetaminophen in arthritis. All

11:59

patients in orbita 1. the two remained on their guideline-directed

12:02

medical therapy, the disease modifying

12:04

drugs like statins and aspirin were not different

12:07

in the two groups. So,

12:09

the main interpretation of these two trials

12:11

is that the current recommendation start

12:13

tablets first for angina and

12:16

then do PCI if symptoms continue

12:19

may systematically select patients for

12:21

whom PCI works poorly. Instead,

12:24

what these trials provocatively

12:26

suggest is that if angina relief

12:28

is the goal, patients could rationally choose

12:31

either tablets or PCI as

12:33

an initial strategy. Both seem

12:35

to work. Now, I worry

12:38

of course that in our American sea

12:40

of overuse, Orbita 2 will be used to

12:42

further increase the amount of PCI

12:45

in stable disease. But

12:47

if that happens, it's not the fault of PCI

12:50

or the Imperial College investigators. Now,

12:53

my perspective on PCI may be a little different

12:56

than a regular cardiologist. I take care of a

12:58

ton of patients with atrial fibrillation.

13:01

So, I see patients with AFib and they

13:04

are now if they have a stent,

13:06

they require both anti-platelets and anticoagulant

13:09

drugs. Now, I

13:11

also see stent thrombosis when these drugs are

13:13

held for bleeding. So, if

13:15

I had chronic stable angin or the discussions

13:17

that I'll have with patients, I

13:20

would likely to try tablets first as

13:22

to avoid having this metal cage in my

13:24

coronary that then requires

13:27

long-term dependence on anti-platelet

13:29

drugs and it will always loom

13:31

as a site of neo-athrosclerosis or

13:33

stent thrombosis. Now,

13:35

finally, I want to remind any new listeners

13:37

or young people that no matter

13:40

the degree of coronary stenosis or number

13:42

of lesions excluding left main,

13:45

there is no compelling evidence that PCI

13:47

reduces heart outcomes over medical

13:50

therapy. The rate of heart attack or

13:52

death is the same if you treat stable

13:54

coronary disease with PCI or

13:57

tablets. So, what we are talking about here is quality

13:59

of life. and symptom relief. PCI

14:02

for stable coronary disease should be done to relieve

14:04

symptoms. Orbita 2 shows

14:07

that it works well as first line therapy. Orbita 1

14:10

shows that it works hardly at all when

14:12

added to maximum medical therapy. I

14:15

think we're going to see a guideline change so

14:17

that patients can be offered PCI

14:20

as first line therapy. All

14:22

right, third topic today is a study

14:25

called Artesia. One

14:27

of the most common questions in cardiology

14:30

is what to do when a device, usually

14:32

a pacemaker or ICD or maybe a loop

14:34

recorder finds asymptomatic short

14:36

duration AFib, say one hour, maybe

14:39

two hours, even eight hours, twelve

14:41

hours. Let's say your patient

14:43

who has this short duration AFib has a

14:46

CHADS VAS score of four. If

14:48

this were clinical AFib, that is,

14:51

this patient came into the office for symptoms

14:53

and had an ECG that showed AFib,

14:56

she would definitely recommend oral anticoagulation

14:58

therapy. You do that because there

15:00

are oodles of trials showing that warfarin

15:02

was better than placebo or aspirin and

15:05

then subsequently, doax were similar to

15:07

or better than warfarin. But,

15:09

but so-called subclinical AF

15:12

is different. It's shorter in duration and

15:15

it's only discovered because of technology.

15:18

We don't even know if it is an actual

15:20

disease or perhaps just a condition of aging.

15:24

The thing is that subclinical

15:26

AFib looks like AFib. When you

15:28

look at the device, the atrial channel

15:30

shows phlegmatory activity. The

15:33

V channel has an irregular rhythm

15:35

when there is an intact AV node. But

15:37

the duration of these electrical episodes

15:40

are shorter and patients rarely feel them. Now,

15:43

at the ESC meeting a couple months ago,

15:46

the NOAA AFNet-6 trial,

15:48

NOAA trial for short of Edoxaban

15:51

versus placebo for patients who add

15:53

subclinical AF found pretty surprising

15:56

results. The DOAC drug

15:58

Edoxaban did not. did not

16:00

significantly reduce the primary endpoint of

16:03

stroke, systemic embolism, or CV death, but

16:05

it did increase the rate of

16:07

major bleeding by a statistically significant 31%.

16:12

NOAA therefore was stopped prematurely

16:14

for both perceived futility

16:16

of efficacy and harm from

16:18

bleeding. Now the

16:21

explanation for NOAA was that subclinical

16:24

AF conferred a very low stroke

16:26

rate of approximately 1% per year. Now

16:30

I know sometimes your

16:33

eyes, my eyes glaze over when we're talking

16:35

about yearly stroke rates. What does that mean 1%

16:37

per year? But I think this is

16:39

an important concept and we use it really every

16:41

day with the CHADS VASSCORE when

16:44

we treat clinical AFib. The

16:46

idea is simple. Oral anticoagulation

16:49

is not free. It does reduce

16:51

stroke, but it also increases bleeding.

16:54

If the CHADS VASSCORE is high enough, then

16:57

we use oral anticoagulation because

16:59

higher CHADS VASSC means a higher

17:02

yearly stroke rate. For instance,

17:04

we estimate, emphasis here

17:07

on estimate, that a CHADS VASSCORE of 2

17:09

means a 2.2% yearly stroke

17:11

rate. And at that level or

17:13

higher levels, we feel that the

17:16

absolute risk decrease of stroke

17:18

from oral anticoagulation is

17:20

outweighed by the absolute bleeding

17:23

rate increase and that leads

17:25

to what we call a net benefit.

17:27

Well, well, if the yearly

17:30

stroke risk is low, then

17:32

the absolute risk decrease

17:34

with oral anticoagulates will

17:37

not outweigh the bleeding rate increase.

17:39

And that is kind of what happened in NOAA. But

17:42

Artesia was a different type of trial, right?

17:45

Here, this is a Pixaban

17:47

versus aspirin. It enrolled more

17:49

patients, 4000 instead of 2500. Artesia

17:53

followed patients for longer and

17:55

they had a more focused endpoint of only

17:57

stroke and systemic embolism. It's

17:59

more of a

17:59

focused than Noah because Noah had stroke,

18:02

systemic embolism and CV death.

18:05

So, Artesia was set up to have more

18:07

stroke events. Now, Artesia

18:09

used aspirin in the control arm when would

18:12

also mitigate the Delta in bleeding

18:14

events, right? Because we know in Averroes

18:17

trial aspirin in epixaban had very

18:19

similar

18:20

bleeding rates.

18:21

So now, let's go into the details of Artesia.

18:24

The average age of patients was pretty old

18:26

at 77 years, slightly

18:28

more than a third of patients were female, the

18:31

mean Chad's VAS score was 3.9, the

18:34

median duration of AFib however was

18:36

only 1.5 hours and only 20%

18:39

of patients had AF duration longer than 6 hours.

18:42

The results

18:44

primary endpoint occurred in 55 of 2015

18:46

patients in the epixaban arm versus 86

18:50

of 1997 patients in the aspirin arm. The percentages are really

18:58

small 0.78% versus 1.24% per patient year. The difference

19:00

of only 31 stroke

19:06

events in a trial of more than 4,000 patients

19:10

yielded however a statistically significant

19:12

relative risk reduction of 37% so the hazard ratio

19:19

0.63 with very tight conference intervals and

19:21

a highly significant P value.

19:23

The authors assessed

19:26

and stressed stroke severity and

19:28

they reported that 18 of 55 strokes

19:31

in the epixaban arm were disabling

19:33

or fatal versus 36 of 84 strokes

19:37

in the aspirin arm so that's 33% versus 43% respectively.

19:39

The relative risk

19:43

reduction for these severe

19:45

strokes that had a modified

19:47

Rankin scale of 3 to 6 was

19:50

a little bit higher at 49% so 37% reduction of stroke and

19:52

systemic glasm

19:55

overall but a 49% reduction

19:59

of really bad strokes. The

20:01

safety endpoint of major bleeding occurred

20:03

in 86 of 1989 patients, that's 4.3% of patients in

20:08

the epixaban arm versus 47 of 1972

20:10

patients, that's 2.3% of patients in the aspirin arm and

20:16

this is in excess of 39 major

20:19

bleeding events. That relative risk

20:21

increase was 80% hazard

20:23

ratio 1.80 with

20:26

really tight conference intervals and a

20:28

highly significant P value. Now,

20:30

the authors also stressed and subdivided

20:33

the bleeding events noting that most bleeding

20:35

events were handled with supportive care, fatal

20:38

bleeding and intracranial bleeding events

20:40

were actually numerically lower, lower

20:42

in the epixaban arm but essentially no different.

20:46

So these significant reductions in stroke and

20:49

bleeding increase led the authors

20:51

to make two types of conclusions.

20:54

The basic conclusion, the one that reads

20:56

in the abstract of the New England paper reads

20:59

quote among patients with subclinical AF,

21:01

a Pixaban resulted in a lower risk of

21:03

stroke or systemic embolism, that

21:06

aspirin but a higher risk of major

21:08

bleeding period, that's it.

21:11

But at the meeting and in the final conclusions

21:13

in the manuscript, the authors ask us

21:15

to consider that

21:17

A, strokes are worse than bleeds,

21:20

B, epixaban reduced

21:23

all strokes but also disabling strokes,

21:26

C, most bleeding events could be managed without

21:29

disability and D, the worst

21:31

bleeds like intracranial hemorrhage or fatal

21:33

bleeding were not increased in

21:35

the epixaban arm and this led them to a couple

21:38

comments. One

21:40

is quote simply

21:42

counting strokes as compared with bleeding events

21:44

might suggest a neutral overall effect.

21:48

They write noting that quote strokes involve

21:50

permanent loss of brain tissue whereas

21:53

major bleeding is usually reversible with most

21:55

patients having a complete recovery. So they're

21:57

making a distinction that

21:59

stroke.

21:59

strokes are worse.

22:01

And then second comment they make

22:04

in the manuscript, in this trial involving

22:06

patients with risk factors for stroke who had

22:08

subclinical AF, a pix of

22:10

band resulted in a lower risk of stroke or

22:13

systemic embolism than aspirin. This

22:15

effect included a substantial between

22:18

group difference in disabling or fatal

22:20

stroke. And then the risk

22:22

of major bleeding was higher with the pix

22:24

of band than with aspirin but most bleeding

22:26

cases responded readily to supportive

22:28

care. Now, I wrote

22:30

an opinion column about this and I differed a

22:33

bit from this preference for anticoagulation.

22:36

I totally understand and get the fact that

22:38

the net benefit leans that way. It does.

22:41

But of course, human beings aren't robots

22:45

looking at risks and benefits

22:47

in pure mathematical terms. The

22:50

absolute risk reduction in stroke and bleeding was

22:52

really small. Risk reduction over 3.5 years

22:54

was about 1.6%. So, that's an

22:58

NNT of 67. The

23:01

risk increase was about 2% or

23:03

number needed to harm a 50.

23:06

So, I think it's a really tough call.

23:08

What I wrote is that when you present this to patients,

23:11

different people will feel differently about it.

23:14

Some patients are more fearful of stroke and they

23:16

would want to have the oral anticoagulant.

23:19

Patients more fearful of bleeding might hold off.

23:21

Keep in mind too that it's not just a calculus

23:24

of stroke and bleeding. Patients also

23:26

have to factor in the burden of taking a twice

23:28

daily pill and accepting

23:31

it's pretty high cost. The

23:34

thing is that this data, both trials combined,

23:36

doesn't allow an algorithm or quality

23:38

measure. There will be no correct

23:41

answers. And I kind of like that. You

23:43

have to talk with your patients and assess

23:45

their goals of care and

23:47

preferences. Now, one thing

23:49

to look forward here is a patient

23:51

level meta-analysis. Dr.

23:54

Bill McIntyre and colleagues, including authors

23:57

of both trials, have published a trial-level

23:59

meta-analysis. analysis. Circulation

24:01

published a study, I'll link to it, and it shows

24:04

that the NOAA and ARTESIA studies are

24:06

entirely consistent. But what

24:08

we really need, I think, is a patient-level

24:10

meta-analysis where they can

24:13

graph the duration of subclinical

24:15

AF with the treatment effect. I

24:18

suspect that that graph will show that a treatment

24:20

effect of oral anticoagulation will

24:22

look better, reach more net benefit

24:25

with the longer duration AF episodes.

24:27

Now, I don't know that for sure, but I think that.

24:30

And I think that because in the TRENDS observational

24:32

study, it took about 5.5 hours

24:35

to see an elevated stroke risk from

24:38

subclinical AF. And in the ASSERT observational

24:40

study, it took even 24 hours

24:43

to see elevated stroke risk. So

24:45

we'll see and we'll learn more from

24:47

the coming studies. Okay,

24:50

I've gone on for a good while, and

24:52

I've only talked about three studies, but these are

24:54

three really major

24:57

studies in cardiology. In the coming

24:59

weeks, not Thanksgiving, we'll take

25:02

Thanksgiving off, but in the coming weeks, I'll

25:04

review the many other papers from AHA, and

25:06

there's certainly a lot to keep us going for

25:09

many weeks. And so that's it for

25:11

this week in cardiology. As

25:13

always, I'm grateful that you listened.

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Thank you. And remember, take

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the time, give this podcast a

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rating at whatever app you use, write

25:23

us a one or two sentence review. These

25:26

things go a long way to helping

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others find us. Until two

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weeks post Thanksgiving, this

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is John Mandrola from the heart.org

25:35

Medscape Cardiology.

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You're listening to this week in cardiology

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from the heart.org Medscape

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Cardiology. This podcast

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is intended for healthcare professionals only. Any

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views expressed are the presenter's own and do

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not necessarily reflect the views of WebMD

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or Medscape.