Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 105 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is unraveling the mystery of P 2y, 12 inhibitors, clinical pearls and comparative evidence. And today we're talking about the P 2y 12 inhibitors, basically a class review and what a typical clinician is going to need to know about, really, these three oral agents that are commonly used on the market. Dr. Khyati Patel 00:54 And we should keep in mind that you may hear different names of these pharmacologic drugs. It could be p 2y 12 receptor antagonist. It could be p2 by 12 inhibitor. It could be ADP receptor antagonist, although there are technically other ADP receptor antagonists than these 3p, two by 12 inhibitors, and then some may also known these as thiono pyridine because of the chemical structure of the drugs. Dr. Sean Kane 01:21 And in all fairness to that last one, ticagrelor, the third one that we'll be talking about isn't even in that drug category, per se, because structurally, it's different that we will talk about. So really, P 2y 12 receptor antagonist, or P 2y 12 inhibitor, is probably the most appropriate term for what we're trying to classify today. Dr. Khyati Patel 01:38 And so the first agent is clopidogrel (brand name Plavix), that was the first one available of this category in 1997 and then a couple more came up, and those were prasugrel (Effient, 2009) and ticagrelor (Brilinta, 2011) Dr. Sean Kane 01:56 and we will acknowledge that there's a fourth agent inside the only that we're not going to talk about today, because really we're comparing these crime comparing these chronic oral Pty 12 inhibitors that are on the market. Yeah. Dr. Khyati Patel 02:06 So kind of the things that we want to address today is, how do these drugs work? Who's indicated to receive these drugs, and what makes them unique, and kind of comparing is one better than the other. Dr. Sean Kane 02:18 So in terms of the pharmacology, the mechanism, as the name would suggest, these are P 2y 12 receptor blockers, and the P 2y 12 receptor is naturally activated by something called ADP, adenosine diphosphate. And ADP is something that's released from platelets when they get excited, right? So during platelet activation, they change their shape, they release ADP, and that process promotes further platelet activation and aggregation. And this is how clots form. This is how atherosclerotic plaques turn into clots that turn into heart attacks and strokes and things like that. So effectively, what we're doing here is we're blocking part of this pathway, so ADP is still formed, but when ADP gets formed, there's no receptor that it can activate because we're blocking that p2 i 12 receptor, giving it an anti platelet effect by calming down the platelet activity and preventing activation and aggregation, right? Dr. Khyati Patel 03:11 And then kinetics are kind of interesting. We call these agents, or most of the p2 i 12 inhibitors are irreversible inhibitors of the ADP. And so really what irreversible means is that platelets will never regain its original functionality. You will have to wait, not until the drug is out of your system. So not pertaining to the half life of the drug, but really when new platelets form, right? So we really are looking at the platelet lifespan, rather than looking at the drugs half life. So here we're talking about five to seven days for platelets to regenerate. Dr. Sean Kane 03:49 When I was a student, I definitely did not appreciate this concept. I assumed that if you had an irreversible inhibitor, that there must be a reversible one, that you could, like, give an antidote that would like, get rid of the drug or something like that. And Dr. Patel, you put it perfectly. Basically, at this point, it's just it will bind covalently to that platelet and never, ever let go, and you have to make new platelets in order for your your platelet effect to come back. And you know, we actually see the same phenomenon with something like aspirin, even though it has a really short half life, it's duration of anti platelet because it covalently binds to those platelets, is a full five to seven days until new platelets are fully formed. So that has implications in terms of if you have a bleeding patient who's on aspirin, let's say, if they just took their aspirin dose and they still have aspirin in their body, they're still going to have an anti platelet effect. But after several hours, once that aspirin is gone, if you gave that patient platelet like a platelet transfusion, those platelets will not have any aspirin attached to them, because the aspirin is out of the blood. It's gone completely. So if someone is bleeding and has been exposed to aspirin, giving platelets is actually a very valid approach, because that anti platelet effect is still active on the. Existing platelets, but any new platelets you give the patient won't be exposed to that drug anymore, right? Dr. Khyati Patel 05:05 And this is a great example of difference between the pharmacokinetic of the drug versus the drugs effect wherever it needs to affect which is, we call it pharmacodynamic effect. So the anti platelet effect is really the pharmacodynamic effect of these anti platelet agents. And so remember when we discussed previous podcasts about anti thrombotics and anti platelets, we talked about how antiplatelets of a patient undergoes a procedure needs to be stopped before five to seven days, and this is exactly the reason why we do that. Dr. Sean Kane 05:34 And then, of course, if we have irreversible inhibitors, it's interesting now that we have reversible inhibitors as well. In the case of ticagrelor Brilinta, it is actually a reversible inhibitor, and in this case, the drug half life would correlate with its antiplatelet effect. Duration of action is slightly shorter than our irreversible inhibitors, but because Brilinta has a pretty good half life in terms of about a day, it does take several days for the antiplatelet effect to go away, not that dissimilar from our other antiplatelet agents, right? Dr. Khyati Patel 06:05 And now we talked about some of the efficacy and mechanism in kinetics, but what about the side effects? So there are antiplatelets, and we're going to see some non serious or non major bleeding and bruising that's relatively very common, although the serious type of bleeding and bruising can also occur with these agents. Dr. Sean Kane 06:24 And when I talk to patients about any of these, p2 i 12 inhibitors, a lot of my Lange and key points are really similar to the same key points that I talk about with any of our anticoagulants. So I say things like, you're more likely to bruise in places that you have no idea why you're getting a bruise when you brush your teeth, if you're too aggressive, or you have a hard bristled brush, you're more likely to see some gum bleeding and things like that. All of those are fairly normal things that are not alarming. And then I go into the don't play football, don't get into high contact sports, and kind of joke with the patient a little bit. But in all seriousness, tell them, if you have an injury, you're more likely to have a serious bleeding event or even have a spontaneous bleeding event. You know, these are not benign therapies. In my mind, these aren't as bad as our anticoagulants, but these are still pretty high up there in terms of risk of bleeding, Dr. Khyati Patel 07:09 and that's why we are selective in who we give these agents to, right? So let's talk about what patients should receive these drugs. Dr. Sean Kane 07:17 So number one, probably the easiest layup indication, is going to be PCI. So someone who had a heart attack that now has a stent placed in a coronary blood vessel, whether it's NSTEMI or STEMI doesn't really matter. This is easily the best indication for these P2Y12 inhibitors in addition to combination with aspirin. So we call this DAPT, or dual antiplatelet therapy. So basically, anyone who's had a coronary stent put in, they should be on a P2Y12 inhibitor plus aspirin, Dr. Khyati Patel 07:45 and any of the three agents can be used. We know that clopidogrel tends to have somewhat lower efficacy but also lower bleeding rate compared to prasugrel or ticagrelor when used with aspirin. And we'll get Dr. Sean Kane 07:57 into a little bit more comparative data later on in the podcast. But basically all three are good and equally preferred by the guidelines Dr. Khyati Patel 08:04 for non invasive. Just for medical management alone, we can use these agents in addition to aspirin. So again, dual antiplatelet therapy. We prefer that we use clopidogrel and not prasugrel in these patients. Dr. Sean Kane 08:19 And basically the only reason for that is that the main prasugrel study looked at people who got stents. So they really haven't done a study in non‑stented patients who were medically managed with an acute MI. Dr. Khyati Patel 08:30 And there are some non mi related indications, such as, you know, post stroke or TIA, or patients who have peripheral arterial disease. Again, most of these data, however, are with clopidogrel over the other two agents, and Dr. Sean Kane 08:45 that's largely a function of like, how long clopidogrel has been on the market for compared to these newer agents. So for the most part, if you're seeing a non mi indication, it's probably going to be clopidogrel that you're going to go with for those patients. So Dr. Patel, one thing that is vastly different from when I was a student is how long we're giving this dual anti platelet therapy for. So when I was a student, I kind of learned, you know, a couple months if you got a bare metal stent, and then a couple more months if you got a drug eluting stent or a des stent. And basically, my understanding is that, as literature has evolved, that time frame for better, for worse, has been extended longer, right? Dr. Khyati Patel 09:22 That's correct. This topic is confusing; thankfully we have guidance from the AHA/ACC that addresses dual antiplatelet therapy. Generally DAPT is recommended for at least 12 months (longer in selected patients, up to 36 months based on ischemic vs bleeding risk). Dr. Sean Kane 09:53 And then, in addition to that, you know, aspirin really should be lifelong therapy, and unless the patient has some kind of RE. And that they shouldn't be given aspirin, like rash, allergy, bleeding event, something along those lines that would preclude them from being indicated for aspirin. Dr. Khyati Patel 10:08 Yeah, remember when we covered the secondary prevention versus primary prevention? Remember when patient undergoes a PCI, or any of these events? Now we are treating them for secondary prevention, so at least single anti platelet therapy with aspirin will be lifelong unless they have contraindication or they've had multiple bleeds. Dr. Sean Kane 10:26 Now, in terms of our Pty 12 inhibitors on the market, we've basically covered the three main ones, but I did want to mention, really the first one. And normally I wouldn't mention this, because it's off the market. It's not really used at all in the US anymore. But the reason that it's important or twofold, one, you know, it was really the progenitor to clopidogrel, and then later on, these other agents. And two, the side effects that we observed in this first drug really have informed our monitoring and worry about some side effects of these more modern drugs as well. So this initial drug is called ticlopidine (Ticlid), and the manufacturer stopped making it several years ago because of its side effect profile. Specifically, it has a lot of boxed warnings that, again, are applicable to some of our newer agents as well. Dr. Khyati Patel 11:13 And so I believe one of the box warning was risk of neutropenia/agranulocytosis, and there was about 2.4% risk of the ANC < 1200 and then 0.8% with ANC < 450 Dr. Sean Kane 11:28 and of course, ANC is absolute neutrophil count — when very low the patient is at risk for infections. Another boxed warning is TTP (thrombotic thrombocytopenic purpura), which features microthrombi that consume platelets and cause microangiopathic hemolysis and organ dysfunction. Dr. Khyati Patel 12:16 and not only the clots in the small blood vessels, there could be micro thrombi and vital organs that could lead to potential life threatening situations such as, you know, liver failure or renal failure, or even bleeding in CNS. Dr. Sean Kane 12:31 And really, I mean, this is rare. The risk of TTP was observed with ticlopidine (Ticlid). Although very uncommon, ticlopidine's safety profile led to boxed warnings and the drug fell out of use. Dr. Khyati Patel 12:42 and one of the other rare ones, like, again, the case of one in many 1000s were aplastic anemia. So basically, the bone marrow shuts down and doesn't make any more vital cells. Dr. Sean Kane 12:53 So given how scary this is, the package insert for ticlopidine (Ticlid) recommended CBC monitoring every 2 weeks for the first three months. Although ticlopidine is rarely used now, TTP can occur with other P2Y12 inhibitors (rarely) and should be watched for. And fortunately, if TTP occurs, it happens within the first couple weeks of therapy. But really, all of our Pty 12 inhibitors potentially can cause something like TTP that providers should be aware of, right? Dr. Khyati Patel 13:30 And so we need to keep an eye on the patient at least for the first few weeks of starting the therapy, because that's where is most likely to occur. So let's talk about what is unique about all these different p2 by 12 inhibitors. And we're going to start out with start out with the oldest and most widely used clopidogrel, or pramix. Dr. Sean Kane 13:46 So in terms of its pharmacokinetics, it is a prodrug. So you take clopidogrel, you only absorb a portion of it. Of that portion you absorb you actually have to convert it in your liver through an enzyme system called CYP2C19 that will activate it into its antiplatelet metabolite that will go out and inhibit the P2Y12 receptor. The problem here is this activation pathway is highly dependent on that one enzyme, and variability causes under‑ or over‑activation of clopidogrel. Dr. Khyati Patel 14:26 So one example is drug interactions — CYP2C19 is susceptible to these drug interactions (omeprazole is the commonly cited example). Genetic variation in CYP2C19 also affects activation of clopidogrel. Dr. Sean Kane 14:47 correct Absolutely. So there are patients that are poor metabolizers or hyper metabolizers through this 2c 19 pathway, and of the drugs that we have pharmacogenomic data for clopidogrel is pretty high up there in terms of. We have a good amount of data showing that there are certain alleles of this enzyme system that make you more likely to not respond to Plavix, or more likely to bleed on Plavix, so much so that the FDA actually has a boxed warning specific to this issue, saying that some patients will be poor metabolizers through this 2c 19 pathway. Generally, you're not going to know if they are or not, but it really highlights one of the first drugs that I'm aware of that is a common drug showing a genomic variant that could impact how well the drug works. Dr. Khyati Patel 15:30 That's pretty interesting to know. We talk about side effects of most P2Y12 agents — the common one is bleeding. But let's talk about unique side effects: clopidogrel can cause hypersensitivity/rash (about 6%). Typical dosing for clopidogrel, if the patient is started in hospital, is a loading dose of 300–600 mg (600 mg for PCI) and maintenance 75 mg daily. Dr. Sean Kane 16:18 with in the case of clopidogrel, at one point, because we knew that certain patients would be poor metabolizers or poor activators of the drug. At one point, we tried to give higher doses of clopidogrel, like a double dose of 150 milligrams a day instead of the 75 when we did that, basically, it didn't work very well. So that isn't typically done and not recommended. Instead, we should be selecting an alternative therapy. An example could be prasugrel or ticagrelor, or Dr. Khyati Patel 16:44 Talking about prasugrel. Let's talk about Effient and what's unique about that. So just like clopidogrel, prasugrel is also a prodrug and requires metabolic activation. However, prasugrel activation is more predictable than clopidogrel and reaches peak effect faster (about 1–1.5 hours vs 2–6 hours for clopidogrel). Dr. Sean Kane 17:13 In terms of what makes prasugrel unique, the main issues are boxed warnings, contraindications and precautions. Prasugrel (Effient) is contraindicated in patients with prior stroke/TIA and is generally avoided (or dose‑reduced) in patients ≥75 years or <60 kg because of higher bleeding risk (5 mg maintenance if <60 kg). Dr. Khyati Patel 18:28 And again, talking about typical dosing, it's similar in fashion to clopidogrel. We use a loading dose (60 mg) and maintain patients on 10 mg daily for prasugrel. Dr. Sean Kane 18:40 So our third agent, ticagrelor (Brilinta). The pharmacology is different — it is not a prodrug and does not require metabolic activation. It is not chemically related to the thienopyridine agents (clopidogrel/prasugrel). Dr. Khyati Patel 19:04 it's a cyclopentyl triazolo pyrimidine. I think I did it. Dr. Sean Kane 19:08 You're right — chemically it's different, so ticagrelor is not a thienopyridine, although it produces the same antiplatelet effect. Dr. Khyati Patel 19:22 And remember, this is a reversible inhibitor of P2Y12 versus the other two (prasugrel and clopidogrel), which are irreversible. Given ticagrelor's parent half‑life (~7 hrs) and active metabolite (~9 hrs), the antiplatelet effect lasts about three days — shorter than the ~5 days with clopidogrel/prasugrel. Dr. Sean Kane 19:53 So potentially, if you had a patient that may need to have a surgical procedure sooner than later, like there could be. An advantage here that you don't have to wait as long, but for the most part, this is not a super clinically relevant issue for most patients, correct? And we should note that its onset is equally fast to that of prostagrel, so about one hour, you're peak antiplatelet effect. But it actually has two really unique side effects that the other agents don't have that I think are pretty interesting. Dr. Khyati Patel 20:19 Right — ticagrelor commonly causes dyspnea (≈14% vs ≈8% with clopidogrel) and can cause ventricular pauses (≈6% vs ≈3.5% with clopidogrel). Be cautious in patients with respiratory disease or conduction abnormalities. Dr. Sean Kane 20:47 And the reason that these two particular side effects are notable is consider the patient population that would be taking tikagrelor, someone who just had a heart attack and now has a stent, and we're giving them a drug that increases the risk that they're going to have shortness of breath in arrhythmias or a ventricular pause event. That's not exactly something that most people are going to be excited to have, because now you don't know. Is it a drug effect that makes you more short of breath, or is it a true problem where maybe your stent has now thrombosed over and you need to go get a new stent placed, right? Dr. Khyati Patel 21:16 Right? And it's kind of scary to discern those two differences, right? Because it could be life threatening. So what's Dr. Sean Kane 21:21 really interesting about these two particular side effects? And again, I'm no medicinal chemist, but I will tell you that ticagrelor has similarities to the chemical structure of adenosine, and I do know a lot about adenosine, which is a drug that we give for certain kinds of arrhythmias. It causes ventricular pauses on purpose. So some people think that some of the side effect profile of shortness of breath and ventricular pauses is due to the chemical similarities to adenosine, the pharmacologic agent we give for arrhythmias. Dr. Khyati Patel 21:48 A lot of the answers lie in medicinal chemistry. Unique about ticagrelor is a reported interaction with aspirin doses >100 mg — higher aspirin doses may reduce ticagrelor efficacy. Dr. Sean Kane 22:15 Now this is a big head scratcher, so almost everyone who takes ticagrelor will be on aspirin. So what happened was, when ticagrelor went to the FDA for approval, they did a subgroup analysis comparing those in North America versus those everywhere else, mostly in Europe. What they found was that ticagrelor did not work as well in North America or the United States versus other countries. And they kind of said, well, why would that be? And the main reason that they came up with was at the time in the US, typical aspirin doses for MI patients were 325 milligrams, and typical doses in Europe were 100 or a lower dose. So they kind of blamed the aspirin dosing as the reason that ticagrelor efficacy wasn't as impressive in the US, and that is kind of the best that they came up with. This essentially led to the FDA approval, but putting a boxed warning on ticagrelor, saying you cannot take this drug with aspirin doses above 100 milligrams, effectively saying you should be on 81 milligrams if you're in the US. So this did create some controversy in terms of, was it really an aspirin dosing thing, or was there something different about the US patient population that makes ticagrelor a less attractive option versus clopidogrel as an example, right? Dr. Khyati Patel 23:23 It is pretty interesting. But in addition to the aspirin interaction, ticagrelor is susceptible to CYP3A4 drug interactions, whereas clopidogrel's activation is CYP2C19‑dependent. Dr. Sean Kane 23:35 So effectively, from a drug interaction standpoint, prasugrel is actually the best‑positioned drug to avoid some of these drug interactions, because we don't rely on CYP3A4 and we don't have the CYP2C19 genomic‑activation issue that affects clopidogrel, right? Dr. Khyati Patel 23:50 And when it comes to dosing for ticagrelor: load 180 mg, maintain 90 mg twice daily (possible 60 mg twice daily after year 1). The other agents (clopidogrel, prasugrel) are once‑daily, which may affect adherence. Dr. Sean Kane 24:18 So Dr. Patel, if I'm a pharmacy student, I'm filling out my care plan on this post to my patient. How am I supposed to pick kind of the best or the most appropriate Pty 12 inhibitor? Do I pick the alphabetically first one or whatever is first on your slides? What is the proper approach here in terms of identifying which agent is most appropriate for a given patient? Dr. Khyati Patel 24:38 Very good question. It was again confusing, because there were so many different trials and subgroup analyzes to kind of find out, okay, is it better in North American patients or European patients, you know, whatnot. We do have the ACS guidelines, which consider clopidogrel, prasugrel and ticagrelor as acceptable options (choice depends on patient factors, bleeding risk, drug interactions, and dosing frequency). Dr. Sean Kane 25:04 don't we go through each one and kind of give some pros and cons of why a provider may pick one agent over the other, starting with clopidogrel, the easy one here is that it's been around for decades. We have tons of data for this. This has always been kind of the control arm of these newer Pty 12 inhibitor studies. So we have a lot of clinical experience with this drug. Dr. Khyati Patel 25:23 Yeah, clopidogrel has been on the market for a long time and shows less bleeding compared with prasugrel or ticagrelor. It may be preferred in patients at higher bleeding risk, while prasugrel/ticagrelor may be chosen for higher ischemic risk (e.g., uncontrolled diabetes). Dr. Sean Kane 25:59 And then, as we mentioned earlier, there is an issue with clopidogrel, that it's a boxed warning that we know that there are genetic variants that make clopidogrel less effective in certain patient populations. Typically, this is more common in Asian patient populations, but can be present in really, any ethnic or racial group. What's really exciting, though, is that there was a new trial published in October 2019 called the popular genetic study. This was a New England Journal of Medicine, and basically what they did in this trial is groundbreaking in the sense that for the longest time, we knew that there was this genetic variant affecting clopidogrel response, but we never really had a trial showing us what is the best approach once you know that. So what they did in this trial was they said, Okay, we're going to do genetic testing on half of the group, and if your 2c 19 phenotype looks good, where we think that you're going to be a Plavix responder, you can have Plavix. If you weren't a good candidate for clopidogrel based on your CYP2C19 genotype, then clinicians would give prasugrel or ticagrelor. The trial compared genotype‑guided therapy versus standard therapy without genotyping. So it's really you could get Plavix, or you could get another Pty 12 inhibitor based on your genome, or forget the genome. Don't test it. Let's just go straight to prasugrel or ticagrelor. That was basically the setup for the trial. Dr. Khyati Patel 27:19 And what did they find? I'm actually curious to know. So what they Dr. Sean Kane 27:23 found was their primary efficacy endpoint was, Did you die? Did you have a heart attack? Did you have a stroke, or did you have a major bleeding event at 12 months? Basically, there was no difference. This was a non inferiority trial, and they met the non inferiority threshold of 2% so it was 5.1% of this kind of bad endpoint among genotype guided therapy versus 5.9% so numerically worse, but again, not inferior, if you got standard therapy where you did not do genomic testing and you just got Effie and or brillenta Dr. Khyati Patel 27:54 And so I believe the like you said, the absolute difference 1.7% it may look like it was kind of worse for The standard of care treatment. However, this was not statistically significant, and it met the p value for non inferiority. Dr. Sean Kane 28:07 Numerically, genotype‑guided therapy (using clopidogrel when CYP2C19 genotype allows) showed similar efficacy and lower bleeding (9.8% vs 12.5% with standard therapy). This supports genotype‑guided selection of P2Y12 therapy in some settings. Dr. Khyati Patel 28:45 So it really boils down to concluding that whether you did the genotyping or didn't do it, the efficacy was more or less, not any different, but we could see significantly different safety outcomes. Yeah. And if Dr. Sean Kane 29:00 you think about it, if you're an insurance company and it costs, let's say, 100 $150 to run a genotyping panel, think about how much money you could save if you could identify these patients that now don't have a major bleeding event because you paid $150 up front to just test and see which P 2y 12 inhibitor is most appropriate Dr. Khyati Patel 29:18 for them, right? Because those hospitalization because of bleed are going to be much more expensive than doing 100 $150 worth of genome test. That $150 Dr. Sean Kane 29:28 is basically the cost of like a Tylenol dose in a hospital, right from a patient standpoint. Dr. Khyati Patel 29:33 You put it really nice in perspective, Dr. Kane, so that Dr. Sean Kane 29:36 is basically clopidogrel. So that that new, popular genetic study is groundbreaking and a really big deal when it comes to pharmacogenomics and the role of pharmacogenomics in Pty 12 inhibitors. Dr. Khyati Patel 29:47 I love that. Okay, let's move on to prasugrel again. Know that there are differences when it comes to age and weight — we generally avoid prasugrel in patients ≥75 years or <60 kg (dose reduction to 5 mg if <60 kg may be considered). But most clinicians are going to prefer the other two agents, or if they have a history of TI or stroke again, because these patients had higher risk of intracranial bleeds, Dr. Sean Kane 30:16 and that's a box warning. Cannot do that in that patient population, right? So this got on the market because of a trial called the Triton temi 38 trial, basically showing that you could reduce the risk of MI strokes and things like that, but at the cost of a worse safety profile versus clopidogrel, meaning more bleeding. Again, this very common double edged sword of kind of finding this happy medium of clotting versus bleeding. In this case, this was a bleedier drug than clopidogrel was, but it was more effective at preventing clots. Dr. Khyati Patel 30:44 And I believe this drug was also studied head‑to‑head with ticagrelor — the ISAR‑REACT 5 trial — which compared prasugrel and ticagrelor among patients who underwent PCI (STEMI or NSTEMI). Dr. Sean Kane 31:01 going to say it right now. October 2019 — this issue of the New England Journal was a big deal for the P2Y12 inhibitor market, because typically new drugs are not compared head‑to‑head. They compare new drug A to whatever this old drug is, in this case, clopidogrel. So for more than a decade, we did not know whether prasugrel or ticagrelor was better, either from a safety or an efficacy standpoint. We could guess based on comparing these two drugs to clopidogrel, but this was groundbreaking, because this is a trial now comparing these two newer agents, really pitting them head Dr. Khyati Patel 31:38 to head. The efficacy outcome (death/MI/stroke at 12 months) was 6.9% with prasugrel vs 9.3% with ticagrelor (HR 1.36, p=0.006); NNT ≈42 for prasugrel vs ticagrelor. Dr. Sean Kane 32:12 This is a big deal — in my practice I see less prasugrel use and more ticagrelor, but ISAR‑REACT 5 (Oct 2019) reported lower ischemic events with prasugrel versus ticagrelor in PCI patients, with similar bleeding rates. That result will likely influence guidelines and practice. Dr. Khyati Patel 32:59 That's a big deal. Wrapping up with ticagrelor, its efficacy was established in the PLATO trial, which showed fewer MIs and a mortality signal versus clopidogrel, with tradeoffs in bleeding depending on the definition used. Dr. Sean Kane 33:34 There are different bleeding definitions in trials (so comparisons vary). Ticagrelor (PLATO) showed improved ischemic outcomes and a mortality signal versus clopidogrel; prasugrel did not show the same mortality benefit. ISAR‑REACT 5 later suggested prasugrel may be superior to ticagrelor for ischemic outcomes in PCI patients. Dr. Khyati Patel 34:05 added the PLATO trial results, right? And keep one thing in mind with ticagrelor, as we discussed earlier, that we have to use aspirin doses <100 mg. This is part of the black box warning as well, and we do concern in patients who have adherence issues that this drug maintenance doses are taken twice daily versus the other two are taken once daily. So we really don't know if it compliance is poor because of twice daily dosing for this particular agent, but theoretically, we can make that conclusion that a patient may have a harder time taking it twice daily. Dr. Sean Kane 34:40 So I think, suffice it to say, there is no clear one word answer of what is the best Pty 12 inhibitor in the market? It's going to depend on patient specific factors. But absolutely, this is now a moving target, as of October 2019, because of these two new trials that have been published. Dr. Khyati Patel 34:55 And we can't wait for the guidelines to kind of an expert to kind of weigh in and put. It in perspective for us. Dr. Sean Kane 35:01 Yeah. So to kind of review and go through some of the key concepts from today's episode, you know these p2, I, 12 inhibitors are definitely commonly added to aspirin, mostly in patients with acute coronary syndrome. So STEMI and STEMI, especially when PCI is done, so when a coronary stent is placed, if there are any other indications for these agents, typically, clopidogrel is going to carry those indications versus the two newer agents are typically not currently being used for these non ACS type indications. Dr. Khyati Patel 35:29 And so clopidogrel (Plavix), which has been the longstanding agent, has variable efficacy mainly because of CYP2C19 genetic variation, but generally shows lower bleeding risk compared with other P2Y12 inhibitors. Dr. Sean Kane 35:50 or effing basically, is only used in PCI patients, and there's three patient groups that are either precautions, dose adjusted or complete contraindications. So age at or above 75 years, body weight less than 60 kilos, or a history of TI or stroke. All of those are effectively poor patient populations for that particular drug. Dr. Khyati Patel 36:10 And distinguishing facts about ticaglare or the brilenda is that they cause these weird side effect of dyspnea and ventricular pauses, which are typically not prevalent with the other p2 by 12 inhibitors. And this has a requirement, and it has a black box warning that must be used with aspirin doses of less than 100 milligram for optimal efficacy. Dr. Sean Kane 36:32 So that really wraps up today's episode. If you want to learn more about the guidelines or these two new October 2019, New England articles, we'll have references at our website, HelixTalk.com, we are available on Twitter at HelixTalk, if you wouldn't mind follow us that way, you can stay up to date with what we're releasing, kind of clinical pearls from previous episodes. We love the five star reviews and iTunes to keep us going and motivate us and have other healthcare providers become more likely to see the podcast. So with that, I'm Dr. Kane Dr. Khyati Patel 37:00 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 37:04 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store. Search for HelixTalk and place your review there Narrator - ? 37:15 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.