February 8, 2023


It’s a pleasure to present to a doctor near klieman who is the director of our cardiac catheterization laboratory and interventional program he’s professor of medicine at weill cornell and our institute of academic medicine and he’ll talk about antiplatelet drugs for how long only after stan’s neil great to have you thanks bill and i’ve got to say doctor zogby

He’s got a double a tough job number one he has a big department to run keep on course and number two his other job is when i’m presenting he’s got to make sure i behave which is truly a challenge so oh okay so listen let’s uh let’s do the easy part first after stents only no not after since only the data are very very clear now from the cure trial clopidogrel

Plus aspirin versus aspen alone for an acute coronary syndrome at least fifteen months you need clopidogrel period the plato trial epidural versus tyco a girl or in patients with an acs well guess what tyco a girl or is better pegasus trial patients within three years after an mi who are stables i’m sorry patients who are between one and three years after an

Mi who are clinically stable benefit is present very clear for a low dose tyco aguilar so that’s the easy part but i’m going to talk mostly about stents because that’s what i do so instanton how long do you have to treat patients well everyone knows the answer it’s a really silly question only problem is no one agrees on the answer so last time i looked which

Was last year there were 12 randomized control trials there were 45 meta analyses that’s for meta analyses per trial on short versus long term dual antiplatelet therapy now think about what that means that means nobody’s got a clue they weren’t all concordant they didn’t agree in fact they weren’t even close on agreement so i haven’t looked this year because i

Said to myself well if there were 45 meta analyses in the last two years what’s the likelihood that number 46 is going to clarify the issue okay well i won’t answer that and it gets worse so this is michelle donahue from from harvard this is last year two years after the dapped trial we’re still debating and then i was putting the talk together i get a dean got

An email and take a look dear neil klieman we present to you i’m completely confused how long do we keep plate patients on antiplatelet agents then it ends with best regards well i had a two-word response dr. zogby won’t let me say but you can imagine my reaction so look let’s clarify things 2017 what do we mean by antiplatelet therapy p2y twelve antagonists

Clip it or grill and more recently procedural or affiant or tech aguilera most term most studies are relatively short term treatment presi grill 15 months in patients undergoing stenting for acs tyke a grill or nine month follow-up well why is that well number one the manufacturers have a timetable if they do really long term trials they cannot get the drugs

To approval and there’s a lot at stake and remember these are publicly held companies so there’s some social responsibility to that – when the subjects start to outlive the investigators it gets really embarrassing the downside is bleeding risk aspirin you’ve heard of that drug it’s been around for about a hundred ten years 2017 there’s no way around it in

Patients with coronary artery disease but of course being a generic drug and really cheap it has no friends it has no proponents no one to stand up for it so of course when people bleed we always blame the aspirin because it’s defenseless and there are trials now evaluating whether we should use p2 y12 antagonists without aspirin par one who knows what par one

Is well it’s a really hot receptor on the human platelet this was the if you’re in the basic or translational world there’s been a tremendous amount of attention to this receptor for a variety of reasons it’s really neat stuff if you read about it this is the primary thrombin receptor on the human platelet and i have long been a proponent of developing drugs that

Target this receptor i’m not smart enough to do it but i was really excited about it that said for app xr is currently available it’s a drug that targets par one but you know the trials have been so equivocal or negative that even though i’ve been really hot about this stuff i have never once prescribed it although there’s one patient whom i did think about using

It okay so just remember the downside is these drugs make you bleed this came out of the lancet this week take a look there’s an inflection point for bleeding risk now obviously the older you are the more frail you get the more likely they are to bleed looks like there’s an inflection point at about age seventy five so first two dots relatively linear then you

Hit about seventy five the risk of bleeding goes up and take a look on your right the severity of the bleeding increases so keep that in mind the older and frailer you get the more the balance changes okay so what about stents today let’s stick to some really basic things ninety-five percent of more of the coronary stents we implant are drug eluting stents and

I’ll post forgive me for saying this they consist of a metal frame which is the scaffold which holds the vessel open a polymer that controls the release of drug and the drug and now all the drug eluting stents we use use sirolimus analogues that interfere with the cell cycle prevent the replication of vascular cells that would otherwise otherwise lead to

Restenosis of course they also prevent the replication of endothelial and endothelial like cells that protect the stent so it’s a two-edged sword oh so i’ve been pressing the wrong button sorry guys i don’t do that in the cath lab so let me let me tell you why we care about this and why it’s a topic of debate so a little bit of a trip back into history so 16

Years ago a guy named suzuki published this study and circulation got a lot of attention sirolimus eluding stents in pigs and dogs and the pigs and dogs did great shown on the top bare metal stents you take a look at those dark things those are stent struts the purple stuff cells growing in around them clinically we call that restenosis it’s a real pain in the

Neck instant restenosis you know clinically isn’t so bad except it produces recurrent symptoms and it’s been tough to deal with down on the bottom drug sirolimus eluding stents take a look dark stuff for stent struts the light purple stuff cells growing in and take a look there aren’t very many cells you see a nice big lumen but you see a thin layer of cells

On top of the struts protecting the struts from blood flow which leads to clotting of the stent okay i’ll put it set it on stun okay so that was great we were in hog heaven and then one of these early trials comes back from switzerland the basket laid study and lo and behold although these guys did a good job putting the stents in take a look they were on

Dual antiplatelet therapy aspirin and clopidogrel bitter grill get stopped and what happens the stents start to clock not a lot of them and they didn’t start to clot the day you stopped the clip it a grill but once you were off it you were at risk and how does this work physiologically well you know the stent doesn’t say oh my god where’s my pretty girl this

Morning i’m gonna show that guy i’m gonna cause a heart attack no that isn’t what happens you know we are clotting systems walk around in a finely tuned balance and you don’t get a little bit of a prothrombotic stimulus for whatever reason you know you’ve got increased inflammatory cascade or volume depleted something bad something that tells the body make a

Little more clotting factors rev up the platelets a little more this morning and boom if you’re not protected the stent clots so what happens well there’s a bit of a firestorm in 2006 people say whoa this is unconscionable well people said that because this would you know these reports started to come in and mostly the problem was that they were unexpected

And when something’s unexpected you generally react more vigorously than to well you know something said well we expected this so the firestorm a lot of studies get published quickly let me show you real quickly what happened this is a patient who died after having a stent come to comes to autopsy the stent is shown here it’s sectioned longitudinally and what

You can see on the top this is not the breakfast taco that dr. jones showed you but yeah i know but i’m gonna screw it up if i use so take a look on top what you see is a clot inside that section of the vessel and that clot occurs in areas of the stent struts that have not yet been covered by endothelial cells down on the bottom you see a section lower in the

Stent the struts are covered there’s endothelium there the stents protected so this got a lot of attention this is largely gotten as to where we are 2006 a firestorm special fda hearings the use of drug looting stents dropped from 95 percent to 75 percent took about two years to recover but fast forward we’re now dealing with another generation of stents that

Are better tolerated take a look on your left this is in a rabbit model this is from dr. reneau firmani what you can see is with a current generation of stents endothelial cell coverage is much better so they’re better tolerated by the vessels they heal better and consequently we have seen many fewer stent thrombosis than we used to 1% at the end of the year

And then probably 0.4 percent per year after that uncommon but still an issue so what do we do today well i got two and a half minutes left let’s talk about the easy stuff first patients on so the minority report patients on oral anticoagulants a fib now you’ve got to put them on dual antiplatelet therapy well that’s three drugs that’s a little scary and in

Fact fortunately this group comprises only 7% of the stented population it’s 7% every time it’s looked at it it’s that number exactly there are two non definitive trials they both indicate that oral anticoagulation plus clopidogrel is the way to go without aspirin going to three drugs puts the bleeding rates well off into the stratosphere upcoming non cardiac

Surgery surgeons always want you to stop the dual antiplatelet therapy fortunately that’s within a year only about 5% of stented population well the real answer is you wait six months surgeon says well want to do it now there’s some negotiation you got to be good at negotiating this stuff you wait six months you stop the clip it agrella or whichever p2y 12

Antagonists you’re using several days before the surgery surgeons always want you to wait two weeks the biology says four days will do it start it up as quickly afterwards as the surgeon will let you bio absorbable scaffolds not very many of these around with the current generation that we use you need at least two to three years of depth because there are

Late thrombosis that occur as these scaffolds dissolve you won’t see very many but when you do see someone with this keep them on dual antiplatelet therapy what about the other 88% the rest of the universe that’s where it gets really unclear there are a large number of small underpowered unblinded and i would like to say misleading trials of highly selected

Patients with limited follow-up that show no advantage for an upfront strategy of prolonging depth beyond six months peter do you want to press these buttons for me yeah okay and as a result some of these stents particularly in europe have gotten approval for use with very short durations of dapped then what happens then the sweetheart registry from sweden

Comes out every stent in sweden is in this registry and what do they do well they did a couple of different analyses they compared three months of therapy with more than three months of therapy take a look big difference in in the rate of death stroke or myocardial infarction the difference is 45 events per thousand patients here thousand patients years if you

Then took the same population compared six months of therapy or more with less than six months there’s still an important difference twenty-two events per thousand patients and then there’s the dap to study the most rigorous of all the trials nearly ten thousand patients in this study to be in this study you’ve got a year of dual antiplatelet therapy and were

Then randomized to ask for a loan or aspirin verses or aspirin plus athena pyridine followed for another 18 months so it’s really thirty months versus twelve months so is there a benefit going beyond a year and here’s the answer yes there is composite endpoint but take a look phil’s coming up here i guess i’m at a time i’ll end with this slide but let’s talk

About it there’s a benefit and you know you can look at this and say well you know there’s a more than a 20% relative difference there is but look at it in absolute terms there’s an absolute 1.1 percent difference so what does that mean that means if someone comes off antiplatelet therapy you’re now going from a four and a half percent risk to a five and a

Half percent risk so yes you’re increasing the risk yes you’ve got to weigh this against the bleeding risk and i don’t have time to go into bleeding risk calculation but it’s not a black and white answer there are patients in whom you’re going to be willing to take this risk if you stop dual antiplatelet therapy you are not automatically consigning a patient

To dying or having an mi you’re reducing you’re increasing their risk by a small amount now in some patients that’s tolerable in younger healthier patients who tolerate their antiplatelet drugs that probably doesn’t make sense in older more informations who’ve got more comorbidities it probably does make sense so i think we’ll stop this there you

Transcribed from video
Antiplatelet Drugs: For How Long? Only After Stents? (Neal S. Kleiman, MD) By Houston Methodist DeBakey CV Education