Originally broadcast June 22, 2021
A case-based discussion on the latest pharmacology approaches in the cath lab.
Drs. Farouc Jaffer, Subhash Banerjee, and Darshan Doshi discuss stent design and the latest pharmacology approaches in the cath lab.
Faculty
Farouc Jaffer
Massachusetts General Hospital
Subhash Banerjee
University of Texas Southwestern Medical Center
Darshan Doshi
Massachusetts General Hospital
mhm Yeah, I want to welcome everyone to our webinar today on stent design and Catalan pharmacology as part of the bio emerged series of talks which has been supported by bio tronic, I'm sure she does. She from the massachusetts General Hospital and I have the pleasure of moderating today's session. We are fortunate to be joined by two of the most well recognized names within our field versus dr Sebastian Banerjee from Ut Southwestern. He's a professor at UT Southwestern and serves as the chief of cardiology and the director of the Cath lab at the V. A. North texas health care system. Next is broke Jaffer, who is my partner in crime at massachusetts General Hospital, he's an associate professor at Harvard Medical School and is the director of all corner interventions at MGH including chronic total occlusion. Uh He's a prolific molecular imager and heads up the translational lab as well. So he will be starting us off with a lecture on optimizing coronary stent design to achieve outstanding Pc I outcomes for at least started selling. Thank you, darsha, it really is a pleasure to be here. It's great to be with you and Subash and the electronic team for allowing us to really spend this hour together. We were grateful that you're joining us and hopefully it'll be educational and fun. Um really too great topics and I get to present the first one which is on optimizing coronary stent designed to achieve outstanding Pc. I outcomes. Um and hopefully we'll have some fun discussion during this hour. These are my disclosures and so what, why do we need to do better with stent design? Aren't stents regulating stents in this era? Great, yes, they are. But despite the incredible improvements that we've witnessed in the last 20 years there is still a persistent adverse event rates related to stents. Even in the modern D. S. Era. This was highlighted by work from dr mahogany and Greg Stone and colleagues um really demonstrating that despite our best in class regulating stance, the first year one mace, your one mace is 5% And then remarkably it persists, it doesn't just drop off and become lower and lower over time, there is a 2% mace incidents per year indefinitely. So someone is 40 or 50 years old. By the time there are 70 years old, they have about a one third chance of having restenosis, possibly due to neo atherosclerosis and other phenomena. And restenosis really is a persistent significant event. Leading to re intervention. We have growing breaking therapy programs, drug coated balloons and bypass. So newer stent designs really have the potential to reduce restenosis by reducing Stensrud thickness, improving polymer biocompatibility and improving the potency of anti aristocratic compounds that are carried by the polymer. So, what we really want to know about drug eluting stents, We really are aiming for a durable PC I outcome with a target 0% Tl R. This entails using image guidance. Really important to reduce restenosis, understanding expansion ranges in stent length, understanding the stent complications such as restenosis, 10 thrombosis, launching, launching a stent in formation and tissue prolapse and then focusing on vessel preparation and calcium treatment critical. Also related to image guidance. With that on the step parameter side, we want to understand conform ability, deliver ability, visibility, Stensrud thickness, understand where the efficacy data and safety data lie to achieve optimal outcomes. And then also understand our advances in depth. Both our potency and for short duration Kourtney stands are really a marvel of bioengineering. We take them for granted now because they're so effective. But in the 90s this really was a tremendous special time for understanding how both closed and open cell stents worked. What they're connector designs were, what would allow flexibility but not allowed too much tissue prolapse and still allowed severability, a really nice article and open heart from Watson. It all really details all of the kind of critical factors that have gone into it. Of course, the key components are the stent itself and the metal characteristics including bio resort herbal scaffolds, which are still a important area of research and emerging clinical use polymers are really evolved to be able to obvious security. The rest in arctic payload that prevents restenosis but also have become increasingly thrombosis resistant. And we have both permanent and biodegradable flavors. And then the drugs mostly have now settled on the line is the entire inhibitors to provide excellent um anti aristocratic properties. So, um, why do we use stents just to kind of go back and understand how we've gotten into this phase of really now, preventing late misdiagnosis. Is that uh plano balloon angioplasty was very effective for non calcified lesions, but in issues where there was high chances of recoil and dissection stance became an immediate lifesaving bailout. However, due to medial vascular smooth muscle cell injury and stretch, you can generate an inflammatory response. Smith muscle cell growth and fibrosis. This will promote Neil hyper drive near invincible hyperplasia, which drug eluting stents are more effective but not perfectly effective against leading to the more common incidence of instant restenosis has a stent complication if there is multiple factors driving incomplete healing, stent thrombosis, as we know, also that are critical. Um my complications of stenting fortunately rare but not zero. So um what really happened in the last five years, you know, for about 10 to 15 years from the late two thousands to about the 2000 and 16 18 range. We really had a stability of excellent performance. It was hard to think that another stent design could actually improve things based on a number of data pieces demonstrating that thickness of stents were important in driving outcomes. A new stent was designed with the ultra thin approach 60 microns. This is the Arciero stent where under 3.5 millimeter diameters or 60 microns strength thickness greater than 3.5 or the more typical 80 microns. Uh This this has a very biocompatible polymer PLL a fully resolved within 24 months and uses cyril amiss with about 80% alluded at the 1st 90 days. And with this recognition that stent strike thickness effects target target lesion, revascularization, stent thrombosis rates. This ended up being one of the first, tends to actually surpass prior longstanding best in class D. S. And we'll go through these studies. But the bio flow and bios to me are really two novel designs to remarkable impact studies that really changed our perspective on whether or not we could do better than really excellent stents but recognizing there's still persistent mace to try to improve upon. So here's the first study, the bio flow five study. This was comparing the ultra thin SCS for syria versus the ES science and this is now three year outcomes. And this is important because I'll close with a meta analysis showing that this is not just a short term benefit but really a durable longer term benefit in these trials that's being observed. This was a 2 to 1 or several versus science uh study including 50% patients who had acute coronary syndromes, 15% bifurcation in 25% moderate severe classification presented by David cans are for the investigators in the Lancet and then three year data most recently published in Jack interventions. You can see here. This is really the key summary slide. The target lesion failure rates by three years are still reduced odds ratio of 40% and this is really an early separation. Okay. It happened pretty early and this is curious, but there is a persistent separation and perhaps even a widening here. When we do landmark analysis showing that you're serious tent tends to have a slower platform, lower rate of mace occurring over time. Why that is the case is really a very important question unknown. Lots of possibilities and we can discuss in the conversation piece. So the next kind of major trial to really understand whether or not being ultra thin and this new design might improve outcomes is in stemming populations. This was the design of the bios to me trial. The slide was far from juan Iglesias who presented the bios to me data 10 sites in Switzerland randomized clinical trial of 407 patients randomized 1 to 1 to the biodegradable palmer, Mersereau durable palmer um science. Um both the one year follow up and then the two year follow up outcomes represented for target mission failure. This is the two year outcomes and I'm sorry, I misspoke it's 1300 patients that were randomized. The 400 patients were um using a prior Beijing analysis approach. And um this was an interesting, really remarkable again, um what was different compared to bio flow is that there really wasn't an early separation kind of in the first week, but really happening over the next 30 days to 60 days. And what's remarkable is this curve is really continuing to separate here with a relative reduction of 42% in the target lesion failure rate. This is out to two years. These were complicated patients, 32 millimeters average stent length, 12% bifurcation. And so I'm really another remarkable study. So to this is in the steamy higher restenosis population and able to really show a very flattened curve especially late, which is again really intriguing. Now recognizing these two trials were really changing the face of what had happened in coronary stenting. Um several meta analyses were performed first by shrivel bangalore, which I will actually show at the end. Um but a more recent contemporary meta analysis also including other ultra thin stents. I'm trying to understand the ultra thin hypothesis To the network men analysis in the R0 really compares favorably to the science, the resolute and also the other ultra thin stance on Newbury and the Baia Lima's biomatrix. And you can see the point estimates you're favoring that there's neutrality with the other stents. And this was a network made analysis importantly, a recent data from the E. H. J. Again from my husband and Greg Stone and dr Ahmad and colleagues 16 trials 20,000 patients 2.5 years now. Really longer follow up, not just that first year and really demonstrating that um all target lesion failure, vessel failure, am I? And target vessel and my all really trending. Um 10 thrombosis. Clinically driven Tl R. And T. V. Are um improved durably over the 2.5 year. Uh follow up there is, you know, this curious signal, non significant of perhaps increase cardiac and non cardiac death really, you know, is not crossing significance here but something to to watch. However, the more prominent endpoint these tend to be small numbers. So they have variable spread. The most important endpoints here being with tlf and T. V. F. Clinically driven tlf and T. V. Are are significantly lower. Um I just want to point out that it's important to also recognize what the stent sizes are. We have this available. Feel free to email me or send me a message on twitter. Um if you'd like a copy of this, we'll be updating this. This was done by the late Patel and laura flannery to graduating fellows. That really gives us the kind of stent profile. So it's important to understand um the stent sizes, the stent expansion ranges because that is a determine of how much hostility ation one can do. And this is a nice chart we have up in every room. Um What about short tap? Just talk briefly on this. But the last time two years have showed just a remarkable set of fantastic studies. Twilight stopped up to smart choice global leaders really demonstrating that there is a similar mace right? When we go with shorter data, either monotherapy with thai caligula or clopidogrel after three months and even as fairly as one month in global leaders and there's no penalty to pay for overall mace. But we went on bleeding 20% reductions Um uh 50% reductions even for this. And again similar Mace results, um similar stent thrombosis results. So it's typically a more high bleeding population for the US. populations. But given the improvements in stent design and the ability of potent dept, we can now feel more and more confident about short and depth regiments. They're going to be further studies ongoing. Um Both with a number of different stents, Pheonix one really led this with the new England Journal one month and then more recently, um, the Tico stent, which has been published in Jama, showed that 33 months adapt in the thai capital and monotherapy was neutral and similar for mace less bleeding. This is your serious tent. Another really intriguing study is the pilots tent did one day of death and then Prasugrel monotherapy with this synergy stent and actually had really nice results with that showing that there was no stent thrombosis in that very specialized pilot study. So I just want to close by uh, showing just, you know, at the end of the day, we've got to be able to use these tents and I'm using and complicated lesions. This was the first us case of the FADA approved or zero. Um in February 2019 We had a patient at mass general who had severe dental disease after his lima. Class three engine on pete lima. Very tortuous. Normally not in heart failure elective. Um They abandoned the prior case due to tortuous city. Um And our target lesion here was just south of the lima touchdown. There is the landing zone right here when we lay it out. But from here to here there is this severe lesion. So we started radio lee and we repaired. We had federal access in case there was any reduction in blood pressure or symptoms, we would have placed mechanical support. Um But here in this area we were able to take our time and you specialist wires micro catheters. We have to use an angular it'd be be one guide because it was a very angular it'd take off at the limit engaged. Yeah. Um Used to guide extender and recognize the landing zone. uh micro catheter jacket wise, you can see the tortuous city. We really put the Arciero to the test here. In this first case, I wasn't sure we're going to be able to deliver, but we were able to wire have stable coronary flowing, tolerated beautifully continued, brought the micro catheter down to gently, very slowly. Um to about this last hook here and then used in our stereo 2.25 13 millimeters which delivered very smoothly um and see dilatation and delivered it smoothly and ultimately ended up with a very nice result here. Clinically. He did a great actually noted that he felt better on the table and had a two reduction class in the internet and finished that one year adapt. So to conclude on the step design, thin struts are a significant step forward and coronary stent technology with a high potential produce restenosis and perhaps 10 thrombosis bio flab and by bio flow five. And bios to animal trials are the first trials to show superiority compared to an E. S. Platform. We do need to understand the mechanistic data whether or not this is really the thin strap part itself or perhaps the very about compatible polymer. And then struts really enable smooth delivery in complex tortuous anatomy as you just saw. So in 2021 we can definitely share this notion that they really, coronary stents are remarkable engineering achievement. Um They're becoming thinner while maintaining excellent scaffolding outcomes. Yet there still is a 2% year for mace and we need to be very cognizant of working to improve that, especially as our patients are younger. Um and we have more complex disease interest rates. Biodegradable polymers can also enable shorter dap regimen. It's important to understand the stent sizing and expansion ranges. And also important to use image guidance because we have multiple randomized trials showing that I have a Scotus can reduce recently like 50 and likely will have the same O. C. T. Finding with aluminum. For and with that there's also a great document for the sky complex PC. I document that I refer to Riley was the first author in C. C. I. With that I thank you for attention. Thank you jennifer Mattson for also some of the information um from recent slide data for the tutor outcomes on the bios to me trail. Thanks so much. Looking forward to the discussion. Yeah. Thank you so much for uh an outstanding lecturer as always. Now your lecturer raised a few topics. I was hoping it's been a little bit of time discussing. Subash was hoping today assurance that as well. Um So one of the stent platforms not discussing uh bare metal stents. And the question I have for you is do you think there's any utility uh for the use of your medicines uh in the contemporary catholic? I think in the regionals and the simple avians, I'm pretty happy with those. Um, but in the coronary world, you know, I think you really, we haven't had a formal consensus paper about formally excluding them, but I think the overall rate has now dropped to zero in our lives, you know, direction. I don't I think the last bare metal stent was probably use three or four years ago with our short dap regimens and the clear biocompatibility and using image guidance. I think we really neutralize the acute thrombosis concerns that we used to have but dBS placement student to be in use. What about juicy bosch and your own lab? Absolutely agree completely. And I think that uh we hardly ever used, but I do want to add one vignette of fact is that you know, we did the V a cooperative study called the Diva study which compared drug looting with his bare metal. And I want to find that out. There was a three years ago breaking a PSC. And it actually didn't. It started off with a debate between me and man as many, many years ago when the young it took a significant amount of time to complete. But it didn't show a difference in terms of target lesion failure or major adverse cardiovascular events, comparing those two platforms for that specific. Having said that, we didn't see a downside to using the Yes. So I think it's become the workhorse platform for most of us. And now you're fixing the natives anyways. Right, who wants to fix of and graft anyway. Good point. So, you know, now for you showed some of the uh, the advances that have taken place with metallic stents now, do you think we've maximized what we can do from instead design perspective when it comes to metallic stents? You know, I really do think that we are starting to hit maybe the absolute peak of what we can do and I think unless there's a new class of materials that is ultimately to kind of develop the material sciences and engineering to be dinner but yet provide the radio expansion will support, we need, We really are hitting in the 60 Micron limited, get very close. There is a 50 microns stand out there and that is also being explored, but I think we're really limited by medals more than anything else. The metallic actually component that being said, I think the next era, the still review is whether or not next generation biodegradable stance cancer to be as an effective alternative. Um, as you know, the mag Norris is still available, being tested in Europe and clinically available and in Europe and as you know, more of a 100 micron on type of all platforms are thinner than entire absorbed. That area of biocompatibility and bio resort ocean is still a fascinating era. I think you all prefer to have a nonmetal based implant if you give us as terrible outcomes. This is absorbed hypothesis. A lot of setbacks in that program that kind of cast a doubt, but um, you know, this is going to be a material spot as the materials get better and the world's capitals get thinner and this might be another area that we can really grow in. Yeah, no, I agree with you mean, just talk a little bit more about by reasonable scaffold. So obviously we know from the absorb story we're transpired, but you know, obviously this seems to be the holy grail for the next phase of sense. I think you know, the challenges are to develop a scaffold that has sufficient radio strength. You also want to be able to visualize it properly. Um Sometimes given how thick these devices are, the deliver ability can be an issue. But I mean, the advantages are, we were to be successful. You know, these stands could potentially be conform a ble and flexible to preserve vessel geometry. Um you don't have to have any foreign material left behind. You can restore functional and ethereal coverage. You can restore physiological visor motion. Um you can also avoid jailing side branches and going back to stenting uh band graphs. Um you can also stand and then such is going to be able to graft these vessels afterwards and then alternatively you can also stand to touch down and not have to worry about trailing in retrograde conduit. So obviously I think it's going to be the next phase in the evolution of sense and Magna areas which is by bio tronic um is a resolvable magnesium scaffold. And so you know, the bio solved family of studies have already been published. Look promising and I agree with you. I think that's probably where our field is heading to. Um Now quick question in terms of the drugs. So do you think there's a difference in the type of line this one has? Do you think there's a difference between zero lameness, several a minus or zero villainous as the drug of choice and rather than expense for I think the entire classic in Henry's I think of them as pretty equal. I think the reasons to choose a specific line this drug maybe its ability to deliver into the polymer payload and its general attachment to on the standard scaffold itself percent metal. Um They haven't been shown to be any different. Um There's also sometimes I. P. Issues behind one or the other in general. They've been very very effective. The main challenge as opposed to you know, drug coated balloons which I'll usually packed the taxi based because the line is drives cannot get enough of a payload to have little fella transferred into the wall. Drug transfer is a major difference. Um You know, because LIMAs is now held by the polymer on the stand in this tent is scratching out the polymer against the wall subliminally you can deliver that sufficient amount of drugs and it's it's a more effective drug, we think more benign vascular while compared to tax taxes. So I think the line in terms of probably here to stay unless there's a new discovery um in the D. C. B. World, that's that's also still an open question. Um The other question for you is, you know, as it pertains to radio strength and consistency. If you go to a website for one stent company, um it shows that there uh stent has the most radial strength compared to another company. And if you go to the competitors company website, it'll say the same thing, but in reverse. And so perhaps you can talk a little bit about some of the aspects that make up radio strength may be closed cell versus open sell the thickness of the stress or other aspects that you think play a role in really determining regular strength. You've touched on a number of them And it is such a critical aspect of you know, insurance, we have optimal outcomes especially as we're spending more and more calcified asians were dealing with osteo disease, large buses and so you know, I think there is no independent kind of on resource for the world to expand their lives just testing all these drugs. I think jOHN artist unused to do that, but we really don't have an independent Okay, so I think a lot of it ends up coming down to one's individual experience of trying different scenarios and one on one understands where circumstance may have vulnerabilities and I think that's important to consider, I think when if one is going to use a thin street extent anymore calcified lesion, so important to optimal vessel preparation and I think that's really where image guidance, scoring direct to me because you know, there are, there is obviously the data is out there by also five and bio semi. Um but you don't want no natural thunderstruck extent has the potential to have less radio students of thinner material, but with adequate, you know, they've done a great job to actually kind of minimise differences and bench top radio strength and calcified vessels and so forth. And then I use that. I'm very attentive because I am in awe lesions but particularly with ultra for instance, to make sure I've done an excellent job to the best of preparation uh for you also show two men analyses in addition to our CTS have demonstrated the superiority of the serial compared to many other spent platforms, particularly as it relates to target target lesion failure. Now, if mechanistic lee if you have to surmise, what do you think accounts for? Yeah, I think it's it's really interesting, you know, I've seen some subgroup analysis that You know there as you know, the R0 has in 60 micron platform under 3.5 mm, mm. Unless 3.5 millimeter stances, 80 microns were hired Is 80 microns for the 3.540 When there's been probably underpowered started with analysis between the 3.5 component and higher versus the 3.0 component and lower The benefits have not really shown that it's only in the 30 over the 35, they're actually both getting benefits. So it makes one thing or what is actually happening here? Is it the thinness itself maybe not for the acute issues um is possible that the, you know in general, we know that larger vessels tend to have lower T. L. R. Is even recording. And so you know that mechanism for 35 is really it's pretty remarkable that you can get a benefit and I think there's a lot of interest in understanding whether or not they're just you know it is just a fantastic polymer combination. It is a unique colony. Maybe it's by compatibility is so good that it is decreasing late restenosis neo africa because all of those curves put them by a semi and bio flow five. There's a suggestion of a continuing divergence for flattening of the curve. And that suggests to me that there is probably a reduction in neo atherosclerosis. We don't have a lot of long term O. C. T. Following up but that's really what we need to understand what those mechanisms are. Okay. Um and then the last question for you is you know you mentioned briefly about short tap duration. So practically speaking how do you decide on when to do short tap and are there specific extent platforms that come through one thing about this? Right? I mean I love to be trial based. So you know, the neonics one was really great to give us that one month option, The FADA for that resident on it. So I think as a big picture, I really focus it on high bleeding with patients. I don't like to consider it the patients who just need to have surgery and 1-2 months. I don't tell them that you know, the strength has been studied and we can just stop. It was to bridge people on candler before elective surgery in these situations or even emergency surgery. Um but if I know someone is truly a high bleeding risk patient renal failure, age, anemia, prior bleeding or you know in your recent leading. um I absolutely will choose one of the sense that's been FDA for short death level. So that's one month for resident on X three months for the synergy stent. I know all these companies are working on short adapt indications. I do think it's overall a class effect. People are just doing a better job implanting stents now with image guidance, baptist poem. So spectacular political monotherapy. If I do political monotherapy I do do peanut typing to make sure that we're not Plavix resistance. Well the start to or start real ales. I definitely don't want to talk to someone who is fully resistant on monotherapy Plavix but for HBR patients there is a clear benefit in the actual reading influence. All right, thank you so much for uh that was incredibly helpful. I think that was a great conversation as it pertains to thank design. So now we're going to be moving on to dr Supachai Banerjee's lecture on catholic pharmacology. Sebastian. Please take it away. Thank you. A hard act to follow Farooq. A wonderful, wonderful dark and I think I learned a lot and great questions and I think that mine is on cardiac catheterization lab pharmacology and not an easy talk to give. So I have devised a unique approach. Hopefully you'll find it interesting is to set some very specialized case being yet so we can revolve and discuss around some finite aspects of uh of managing patients in the catholic and the complex biological matrix and the various drug mechanisms do set a set us as set us for a great uh an interesting hopefully conversation. I do have my disclosures but I have a disclaimer also said that some of the things that I might discuss or you might find in my presentation maybe outside, slightly outside the scope of published guidelines. Hopefully there'll be a great prelude to some criticism and very interesting question. Q. And A. I'm sure dash has in store for us. Uh So let me start off. I have three cases too short and one long case. And I'm going to start off with my first case scenario. The idea is not to stump anyone with these questions but simply to put some finite options around this case scenarios and use established data and evidence to derive some conclusions. So the first case is regarding a 78 year old male who was seen at a rural hospital emergency room at eight p.m. For chest discomfort lasting an hour admission ScG reveals science rhythm and inferior SD segment elevation. As the nearest PC. I. Capable hospital is over three hours away. A single ivy bolas after negative place is administered with the significant reduction in the S. T. Segment elevation and resolution of the patient's chest pain. He's also given 325 mg of aspirin and intravenous, unfair action it heparin. The patient is then transferred to your Pc. I. Capable hospital next morning and corny and geography is performed soon thereafter, which reveals a 90% miss RCs stenosis. In addition to performing a successful PC with a single D. Yes. Which of the following is most appropriate in this clinical setting. And I think the choices I've mentioned here include 60 mg of prasugrel, 75 mg of clopidogrel, six loading dose of clopidogrel, 600 mg 300 mg of clopidogrel and 10 mg of practical. All of these options simply to confuse you but also to help you derive at the right uh thought process which would be a patient who is had a PC. I in your lab after being transferred from outside after receiving from politics. So let me go over my simple schematic that might help you recall this at a time of need and which is that during fiber license for stemming. One thing that is, that's that's that is important to recognize is the age of the patient that the that the dose of the initial P two y 12 in a bitter in addition to aspirin and unstructured happened is is the recommendation is directly related to the age of the patient with a 300 mg loading dose of clopidogrel uh for age under 75 years and for 75 more. The political doses actually 75 mg only. And the minimum duration recommended by the guidelines not indicated on this scheme is actually two weeks and you could of course called longer in patients who pursue the detainees coronary intervention and in those patients who have received clopidogrel during fiber analysis. And most likely I'm talking about five specific fiber license in the current era. Uh and those patients can if the later required a rescue P. C. I. Or a R. EPC I. By itself for a farm of invasive approach. For example, they can simply be treated with 75 mg of clopidogrel thereafter. Now, the the more interesting part is for those patients who have not received a P two y 12 in a bitter at the local rural hospital, which is actually the most common scenario whenever we see them being transferred at least in the state of texas. Uh and I think when you see such patients, what is really important is to recognize the duration of time between their fiber and ISIS and PC. I and I think the guidelines clearly differentiate at 24 are mark patients who have had no puppet Gabriel doing five or ISIS if they're undergoing PC I in your lab Within the 24 hours of fiber license at 300 mg of clopidogrel load is indicated. I mean clopidogrel not by cattle or not Prasugrel and I think if the duration has been greater than 24 hours, then there are and the patient has been using a fiber in specific uh tumble ISIS. I think clopidogrel 600 mg or in the absence of obvious contraindications of stroke a tia and other country indication in black box warning for prasugrel, A 60 mg of process could be advised in this patient. So this is my scheme, but I just want to make sure for accuracy purposes. I highlight the actual document and I've highlighted Uh two very important aspects. one I mentioned is the age of the individual to recognize. And then second is the time for private license to pc. I if you remember those two aspects, I think this would be a fairly straightforward question. And I think josh mentioned it to me once before that he probably had seen something very similar in his uh channel cardiology or interventional boards and makes for a great test question. And I think that that given the fact that this is not an unusual scenario, especially where I live, which is surrounded by some very large rule distant communities. I think this information hopefully you will find a useful to recall at a given point in time. So let me move on to my second case vignette here And this scenario and here is the answer. For example. I mean I think I definitely should mention and highlight that because this patient did not receive a fiber isis and he was undergoing TCI within 24 hours I think administering 300 mg of clopidogrel is the right answer and the right choice for the uh for this particular patient. Yeah. Clinical scenario to this is during PC. I. Of a high risk non stem E a 68 year old uh woman receives multiple doses of intravenous morphine sulfate. In addition to ivy nitroglycerin and furosemide for acute management of heart failure. Not an unusual scenario. Any cath lab. I presume she also received aspirin and unfair action. It happened at the local hospital. She lives intubated and is directly taken to the Cath lab. And an intra aortic balloon pump is placed. We have federal access and right radial PC to the middle lead with an geographic tram bus and to me to flow is performed using a drug eluting stent and the patient is also started on ivy carol or during spc following successful completion of the fee ci which antibiotic regimen would be, would make more sense and have some choices for you here. The first choices. Prasugrel 6 60 mg. We are the N. G. Tube if the patient has two hours after discontinuing the kangaroo or infusion. Second is clopidogrel 600 mg. We are N. G. Tube 30 minutes after candle or discontinuation. The third option is to like a girl or 180 mg. We are the N. G. Tube with initiation of the kangaroo infusion clopidogrel 75 the N. G. Tube 30 minutes after and then perhaps a grilled by mouth after The patient has been weaned off of the opioids and it actually can take oral medications. So all of these choices could be considered. And I'm sure many of you have actually faced this type of political scenario. What the real intent here is to highlight uh four basic facts. What are the key decision drivers for NPC I operator when patients undergoing PC in our labs have been exposed to hide those opioids. We also need to consider reliable P two vital inhibition and of course do in and then continuation on from an ivy dozing and then to an oral long term or longer term duration of P. Two vital innovation and think about ADP receptor occupancy. So these three I think factoids make a great setup for a good farmer co therapy question for the Cath lab. So so here are here's my very simplistic scheme. I have tried to take off any published complex receptor diagrams and tried to highlight this ADP binding site for the P. Two vital receptor on panel A. And B. And try to give you some leads on this. And the ADP binds to the actual vital receptor. P. Two vital receptor which fundamentally leads to a confirmation I'll change and g putting activation onto the panel A. I'm trying to depict the active metabolites of clopidogrel and prasugrel occupy the A. D. B binding site, as does Kangol or anti kabila, on the other hand, binds irreversibly to the P. Two vital site but at a site distinct from the A. D. B binding site. And I think that leads to some options that we could think of. The yellow uh shows the yellow show has shown the occupied 80 binding site with might prevent with candle or which might prevent the clopidogrel and practical active metabolized to bind. Whereas the regular binds to the al aesthetic binding site of the vital receptor. And and actually non competing with kangaroo which is a intravenous analog of 80 P. Uh The real binding nature of kangaroo or is still hotly debated. But what is known is that it when infused in the active phase with a short flight, it does prevent binding of a DB at the ADP receptor. So here are some important factoids but I think you can carry over and maybe recall at the time that is needed. First is that the morphine and other opioids definitely delay and attenuate exposure an action of ROP two vital inhibitors. And this is most likely secondary to delayed gastric emptying. And in this clinical situation parental P. Two vital in inhibition advice. I use the word advice but I think most of us should consider it as the operator did. In my case example, the second factor to remember that crushed that are actually randomized studies that have studied crushed clopidogrel Prasugrel and to catalog delivered via N. G. Tube. They actually achieved reliable platelet inhibition in vivo. Both and I think that has been done in comparison with other agents and between agents. So I think that is something also very important and you don't have to really wait for the patient to wake up and a reliable dose can be delivered. The third factor it is that clopidogrel and Prasugrel are pro drugs and active metabolites of Prasugrel have a substantially longer elimination half life than clopidogrel. An important fact that I'll re emphasis a bit later and both buying to the platelet P. Two white well receptor 80 binding site. However as I said tie casual or binds to the P two vital receptor al aesthetic binding sites and hence it may not compete and does not compete with candler and kangaroo or binding site. And I said at the level of the two vital receptor is not definitely known however it has etcetera occupancy and prevents ABP signaling. Another fact that I think is worth remembering and recalling is the hype lately turnover rate and how it affects receptor occupancy and also the half life of the elimination half life of various p two vital agents especially Prospect. And I think where uh there are two I think take on messages from this case one is certainly is the direct answer to the question which is in this case you recognize is that like a girl or 180 mg we have the N. G. Tube would be the right choice. But I think this information that I've tried to share here could also be applied when we make switches with escalation and de escalation between two or three P. Two by 12 agents. And a classic example would be that in a chronic and stable patient when you are switching from say prasugrel to clopidogrel, you may not need to give a loading dose because of longer half life of the past several metabolites 24 hours later. However you may have to do so when you are doing so acutely for some reason because of the faster turnover are platelets in an A. C. S. And an acute setting. So I think those these hopefully these factories however slightly complex but make a problem for michael pharmacologic sense. And by using these case examples, the idea is to highlight them without going through some complicated schematics which kind I think can be laborious to understand and make what another interesting webinar. So I want to launch into my third case. I hope you're enjoying these cases and if you don't and you have comments, I'm eager to hear them at the end of this presentation. Hell is my third case, which I think is a slightly longer one. And just bear with me. This is a rapid high sensitivity troponin essays positive for elevated on a 64 year old man with known diet controlled diabetes mellitus and are no home medications. He is admitted directly from the primary care clinic for new onset chest pain, chest tightness that has been accelerating and associated with moderate severity dystonia in two hours. The repeat high sensitivity, high sensitivity trip on S. A. Has tripled his admission scG is shown below in the figure. And in addition to a planned immediate invasive strategy that the cardiology council team recommends which are the following should be administered to the patient along with aspirin. So basically the choices from A. To F. Are trying to analyze. Would you or would you not uh pre load pre treat this patient if you do so? What would be your agent? And I and I think that this is a classic presentation of a patient with non stem E. As highlighted on the BCG with ischemic changes. And the direct question here is that are you a believer or a nonbeliever? And I think through this question, I wanted to highlight an interesting discussion point that uh that goes to the foundation of our of this case and also hopefully to the Q. And A. That will ensue that by based on the most recent iteration of the non SD second elevation A. C. S. H. A. C. C. Guideline A loading those P two Y 12 receptor inhibitor should be given before the procedure in patients undergoing PC. I withstanding. It is also shown on the schematic and it would not be incorrect to give this patient one of the drugs that you choose and then take him to the cath lab. And of course there are some specific agents that we may or may not choose in this clinical scenario. However, the PSC guideline recommendations which have a little bit more recent, of course it's state that it is not recommended to administer routine pretreatment with P two Y 12th receptor inhibitor in patients in whom Corey anatomy is not known and an early invasive management this plan and it's not actually P two Y 12 agents specific. This is a general recommendation going further. It also provides some recommendations regarding a specific agent uh using our preferring process grow in preference to tie kagle or for non sDA CS. And patients who proceed to PC. Which is I think at this current point is a departure from a. C. C. A. J. Guidelines. So let me take it further and and try to first define the word pre treatment. So how do we really defined pre treatment? Is it before the patient goes to the lab or between angiography and D. C. I. And I think I personally refer to two studies that have defined this quite clearly. One is the our media and the second is shown on the slide. A cost we shall discuss like in great detail in our media which is not shown here. The clopidogrel was loaded 6-8 hours before the patient went to the lab in one arm and the second arm was after diagnostic cory angiography was performed in an unstable lord was given to the patient before proceeding to P. C. I. And I think there was no difference in outcomes in that study. And here is a more recent study. A slightly more recent study 2013 where a smaller dose of prasugrel was given 30 mg before angiography. And that was the definition of the pre treatment group are placebo in the control group. And when PC. I. Was indicated an additional 30 mg was given in the pre treatment group while the control group received a 60 mg of prasugrel before proceeding to PC. As you can see in the images the rate of primary efficacy endpoint of cardiovascular death. My non fatal myocardial infraction stroke, urgent coronary revascularization. Or use the R. G. B. Two B. Three. Rescue to seven days did not absolutely differ. However there was a slightly higher or significantly higher uh timmy major bleed with the pre treatment. So that's one piece of evidence. Another more recent study that has that is very intriguing. Which perhaps in my opinion uh goes to the foundation of the E. S. C. Recommendation perhaps is from Aisa react five. And I want to draw your attention to the overall is a react five. But also to the substantial numbers. Nearly 60% of patients including the study did not have a steady so there are unstable angina or non SD. And in that group the thai kagera was given before angiography and procedural after angiography prior to PC. Here are the primary efficacy endpoints of death and stroke clearly outlining in the intention to treat analysis the superiority of prasugrel over taika galore. Now I want to make some comments. First of all I want to say that I have a huge fan of the study because investigator initiated studies do have a special role for each one of us who are investigators also, they tend to ask the most more pertinent and and thought provoking questions. But I think this study had some unique teachers that I want to share with you. Number one, that the bark major bleeding race are shown here 5.4% with caligula and 4.8% with prasugrel. And the benefit of Prasugrel was not a company was not accompanied with an increase in major bleeding as we have been accustomed to seeing in many other trials. Well, uh, this slide may not be the best light, but a lot of work has gone behind trying to show the study size size on the, on the left Vertical access and the relative waste reduction and simply trying to compare less potent agents to more important agent was just two more to relatively important agents in icy back five and a steep distinction in the observed relative risk reduction with 1/4 of the size of comparative studies. The .2, I would say, is I found quite interesting. Second, is that the benefit of possible overtake angle or was not universal. And there was a significant interaction between the treatment dumb and the presence of diabetes as a baseline risk factor. While there was a benefit of prasugrel over to casual or as shown in the figure in non diabetic arm, there was a lack of such benefit of tech, a girl or a possible attack a galore in the diabetic cohort, which I found quite interesting digging a little deeper. I think I found some interesting take on points which I think I want to share number one, that the in a large number of a substantial number of patients, about 2000 patients were randomly uh including in each group, But about 230 patients did not receive. Uh the possibly loading those and and the more and the explanation that was provided was that there that and geographically did did not seem to be requiring NPC. Although their initial diagnosis was A. C. S. The second was that a large number of nearly a third of patients in either arm of the study actually did not complete the study follow up. Being on the assigned study drug. As you can see, the denominator highlights the number of patients in each group. Take 220 12 in Tai Kok Galore and 2006 in the processor alarm randomized. And then the numerator is accumulative summation of the patients not discharged and those who discontinued the drug pose discharge giving an approximate 30% odd. A third of patients were either not just a or not receive the complete the full duration. And then that calls into question some of this data I think, which is interesting. And when these patients actually discontinued the drug has shown on this table for About 50% switch to clopidogrel. And and if you really look in the paper on the on treatment analysis, the hazard rate is 1.34 and it actually crosses unity. I do understand that, that the intention to treat analysis is probably the more formal way of assessing. But I think uh knowing some of these deep facts of about the study might might help you better understand this data and also divide variation. Why the pre treatment of patients prior to going to the Catalan may not be as universal as one may seem based upon the guideline recommendations. Let me say one more piece about this about a syriac five I think the composite endpoint, the primary endpoint of death, non fatal micro infraction and stroke as I mentioned here and the real difference between the two arms of the study between try category impossible was really driven by the differences and rates of nonfatal micro infraction and a large proportion of these smes were actually type for micro infraction. So I think another very very interesting facts. So I think uh let me go back to the question and I want to give you all Maybe 10 seconds to think about maybe Darsch. Uh you want to pick a pick here and what do you think? What would have been your choice? I don't want to stump you here, but uh I'm going to share. You know, my choice of course based upon the evidence I've shared and and maybe I'm leading you to that answer and you don't have to agree with me. But I would say that the evidence for for pre treatment for patients and pre loading them uh prior to going to the lab, despite the fact that the patient is going for immediate or early invasive strategy may not be as universal. I'm sure uh the practice of your lab between operators could be also very different. So I'll I want to hold there and uh and the past date on to you. I just have a final message that applied clinical pharmacology, pharmacology for the cath lab can be a dry topic. But however, I think these clinical scenarios hopefully have made it slightly more interesting discussion. And of course, given prelude to some interesting comments from my uh my uh faculty here and also from the attendees. I do believe that that interpretation of pharmacologic facts and clinical trial require a prepared mind. And, and I think one can always find what he's looking for and interpret the data the way they seem fit. I want to pass the the floor over back to our moderator and I'm sure he's going to enlighten us with his thoughtful comments and then ask me some very difficult questions over to you. All right, thank you so much. Subash you covered an incredibly expansive topic in a very meaningful way. And I wanted to ask you some questions as well as pharaoh. So you know, your last scenario bought up the idea of pre loading with that. It was once thought to be an anathema to not primo. However pre loading has recently come under a lot of fire with a wide variation in practice. So in your own practice you botched you pre load um, why or why not? And then I want to ask my colleague uh approach after two wings. I actually don't but I would submit very easily that there are a lot of smart people in my institution at UT Southwestern Via and Parkland, all three that who do you and I and they actually believe in this data and they would prefer one drop of one another. But I personally don't for the reason that I've tried to highlight both on the basis of randomized trials and also on the basis of registry data from from Scandinavia. Mhm. What about yourself Fj. You on me. Um Yeah I think this is a great question. It's amazing helpful circle. It came of course, never used to do that. And then when we had the pivotal studies with cure coming out really to start this process, we really have to think about it. We always had the concern though potential surgical delays if we had surgical anatomy found at the time of diagnostic angiography, we're looking at five days with prasugrel, seven days of delay. Sometimes patients could be vulnerable during their time. So it created a difficult kind of tension between cardiac surgery and cardiology. Um There were different approaches to that. Some surgeons were willing to operate on dat earlier. Some said you know, we definitely needed to wait it out. My practice is in stable angina and steamy. I absolutely will not pre load, I do not think there is any benefit. Um And steamy there is just as soon as you eloquently discussed, Opiate reduction of absorption is high. It takes 2-4 hours to get peak levels. At that time we have great ivy farmer co therapy for going to wreck to the lab immediately for a steamy. We have access to candler and 23 antagonists. We'll get both adapt with no penalty For potential surgical anatomy. Every now and then in a stem me, we do a primary angioplasty and send the patient to stage surgery a few days later. It's nice not to have to wait 5-7 days. The second, the third category of unstable angina, A. CS non stem me. My personal practices like sabbath as I do not pre load unless I think I'm going to have a high chance of medical therapy or I didn't, I don't think this person is revascularization candidates and I'm taking a medical approach to non stem me then I definitely will if it's an invasive approach and it's going to be timely within 24 hours, very comfortable with not pre loading to have to avoid the penalty of a surgical delay. And in general with, you know, the excellent work in the medical therapy, high dose statin therapy, efficient cath lab management and a junk too far Michael therapy in the Cath lab, we can do a great job avoid the penalty of pre moving. Yeah, I mean, again, my own strategy has been very similar to yours FDA um, in the sense that Campbell has sort of changed the paradigm for me. Um, the fact that, you know, you have almost immediately reverse book to I-12 ambition. Um, and should you want to send the patient for procedure afterwards and as such as cabbage, uh, you know, you're not getting any grief from the surgeons or there isn't a plan for surgery. Um coming back to you, uh, topic not discussed as of yet. It's the role of to be three inhibitors. You think they still serve a function in the catholic, particularly as it pertains to, you know, other types of technology to deal with wrong but such as mechanical aspiration and joe jack's family. The one line answer is less and less and I think that's that's the most simplest answer. And I think upstream is of course gone in lab in rare situation except and not definitely in being graphs. That is clear harm in that category of patients. But I do as you said, that more aggressive and more effective come back to me strategies. I don't want to name devices, but uh, and the use of I I can't roll for patients who are not protected within ADP receptor antagonists. I think give us wonderful options with short half lives that have nearly I would say limited the role of to be three days, at least in my practice, I'm sure uh, in a much wider scale. So uh huh For same as yours, heavily tilted towards Kangol or especially in elderly patients, failure patients, renal failure patients. Those at higher bleeding risk. But for a garden variety stem ease. Um There is a higher potency platelet inhibition with two B three A activity to be 38 Antagonists such as terrified and or up to five outside. And um for young patients radial axis, I'm very happy to do a brief infusion of 2 to 4 hours. I think I get pharmacologically slightly more playing an ambition um compared to qiang galore. But I do think about the bleeding risk. I always do short term infusion. So really not not more than 2 to 4 hours. That's in line with a brief pc. I study girl, that's exactly our practice brief infusion for four hours uh rarely needed. Again I think you know this is a topic that we can spend hours upon but I think we're at the end of our our so any final comments from you pharaoh core from scratch? Uh, I just want to thank you Doris for really doing a great job to moderate this and and stimulate the discussion. I learned a lot from Sasha's talk and I appreciate the questions. I hope it was really informative. It's really a great chance to interact with you guys and it takes to buy tronic for supporting it. I do want to add uh by chronic for supporting it also giving us a complete open and free card to, to device and and and construct our talks and lectures and I do feel that the detailed insight we get from data and reviewing the data and and published studies are very, very meaningful and hopefully our audience enjoyed us trying to capitalize some of those highlights from these large studies that jennifer and I have tried to put together a dark, I want to also say you are you are a tough moderator behind like while signs a welled up deep, insightful questions. So I think requires some thought and deliberation. So thank you for raising some very important points in today's discussion. Thank you. It has been my personal privilege to be showing the floor with Youtube giants. Um and I also want to thank by Tronic to their support as well. The by emerged series is available online. So not only this episode or this webinar but the prior ones are available online. Um and we look forward to welcoming you at the next version. Thank you so much. Take care of a great man. Thank you. Mhm.
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