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 172 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is Battle of the clot busters, alteplase versus tenecteplase for acute ischemic stroke. So today we're clearly talking about two commonly used drug therapies for acute ischemic stroke management and Dr. Patel. This has become a really hot topic. Our hospital system has recently actually switched from alteplase to tenecteplase, and I'm guessing many other hospital systems are also either making the move or contemplating the move. So based on that, the logical question is, why are we doing this? And what do we need to know about this newer drug, connective place for acute ischemic stroke? Dr. Khyati Patel 01:12 And I believe this was our listener requested topic. Dr. Sean Kane 01:15 It was, yeah, we got a request about this. And you know, for any listener that has their own topic that they would like to know more about. You're welcome to contact us at HelixTalk.com, or on Twitter at HelixTalk. So really, the nature of today's episode is to talk about what is the difference between alteplase versus tenecteplase is one more effective is one safer, one cheaper. What is the evidence to support tenecteplase like clearly there must be some evidence to dethrone the king of alteplase, which we've had for a really long time. And then really, what do pharmacists and other healthcare providers need to know about the use of thrombolytics, TPA and acute ischemic strokes? We'll cover kind of the nuts and bolts of using thrombolytics for stroke patients. Dr. Khyati Patel 01:59 That sounds great. And I think breaking it down from the basics, let's discuss what TPA is, and it stands for tissue plasminogen activator. So basically, alteplase is what we work with. It's a recombinant DNA version of a naturally occurring human enzyme, which is TPA. Yeah. Dr. Sean Kane 02:17 So like, TPA is what you normally have in your body. Is that we give you a lot more of it, in the form of a drug called TPA or alteplase. And really the role is that you take plasminogen, which is an inactive protein in your body, and TPA will convert that into plasmin, and that plasmin goes and finds fibrin based clots, and then dissolves those clots. It lyses the clots for you, Dr. Khyati Patel 02:40 yeah, and this is my favorite question to ask when students are in my rotation, because we do manage outpatient anticoagulation as to what's the mechanism of action of those anticoagulants. So if we think about the common clotting pathway, you know, none of those drugs. So we have, you know, warfarin, we have enoxaparin, the 10 a inhibitors, the oral 10, a inhibitors, the doacs, none of them work to break the clot. They are basically working to prevent the existing clot from growing or the new clots from forming. And really, the existing clots are getting degraded by our own body. But some students tend to believe that Warfarin is a clot breaking medication, and that's not true. The clot breakers are really what we are talking about Dr. Sean Kane 03:24 today, and that is a very unique mechanism, and that's where we get the term of a clot busting therapy or a thrombolytic therapy, is that it is a completely unique mechanism. Now, historically, at one point, Patel, we had something called streptokinase on the market, which we basically don't use anymore, but now we have alteplase or activase as a brand name. And basically since the late 1990s this was the drug that we gave for stroke, but then tenecteplase, or T and K ace, the brand name, came onto the market, and it's potentially dethroning alteplase as the treatment of choice for acute ischemic stroke, which is what we're talking Dr. Khyati Patel 04:00 about today. And so I remember back in the day Dr. Kane, I don't work in this environment, acute environment, so whatever I remember about alteplase is from, you know, back in pharmacy school. But in general, I remember that you have to be really careful in choosing a patient that qualifies for a TPA treatment. There's specific inclusion and exclusion criteria. Can we break that down a little bit? Dr. Sean Kane 04:24 Yeah, and I should just mention that these drugs are used for other things as well. So the list we're about to go through is just for acute ischemic stroke. The classic example of a different indication would be a massive pulmonary embolism, and the list of inclusion and exclusion criteria don't apply for a pulmonary embolism patient. So we're just talking about acute ischemic stroke. So thinking about who should get a thrombolytic for acute ischemic stroke? One is that you have to have a stroke, and that makes sense, right? Like you have to have a neurologic deficit, ideally, one that is bad enough that you are willing to risk taking a drug. That increases the risk of bleeding, right? So if it's very mild, you might not choose to give a thrombolytic, although I would say, in the last decade or two, we're giving it to more patients with more mild stroke symptoms, but you at least need a neurologic deficit to earn a thrombolytic like TPA Dr. Khyati Patel 05:17 and the other one I remember, because time is brain, there is some time factor associated with that. So normally we are looking at that the symptoms were starting within last 4.5 hours. In some cases, be even considered three hour as the window to give the TPA, yeah. Dr. Sean Kane 05:33 So originally it was a three hour window, and then a new trial came out after that original trial that extended the window to four and a half hours, but that three to four and a half hour window has more stringent criteria. So as an example, if you're too old, if you're more than 80, or if you have a very severe stroke, your NIH Stroke Scale Score is more than 25 you can't have a history of stroke plus diabetes. And there's other things as well, but the main one is going to be the age stroke severity and a history stroke plus diabetes is a history. For those patients, they don't get the extended four and a half hour window. They have to have stroke symptom onset to TPA within three hours instead of four and a half hours. Dr. Khyati Patel 06:16 And then on the opposite side, we have some exclusion criteria, so we're making sure that patients don't have these things in order for them to receive the TPA. Dr. Sean Kane 06:26 Yeah, so assuming that they have all of those things, now we're going to go through a list of things that they cannot have, and if they do have these things, they don't qualify for TPA. So you know about 80% of strokes are acute, ischemic strokes, but roughly 10 to 20% of them are hemorrhagic strokes, where it's a bleeding problem, not a clot and an artery problem. So clearly, we don't get want to give something to dissolve blood clots if you're bleeding in your brain. So everyone will get a head CT that has a stroke to see what kind of stroke they're having, because you can't tell just based on looking at the patient. Dr. Khyati Patel 07:00 And then the other one is, obviously, you know, no history of having any bleeding in the brain. We're looking for that as well. Dr. Sean Kane 07:06 And then things like surgery. So you can't have recent within three months, a stroke, head trauma, or brain or spinal surgery, because, again, we're worried about you bleeding into your brain or spine, which could cause other problems. Dr. Khyati Patel 07:18 We are looking for good blood pressure control as well. So if the blood pressure is too high, like I'm talking 185 of systolic, 110 or diastolic or above, those patients will also not qualify. Dr. Sean Kane 07:30 And that sounds like a really scary number, but actually a ton of patients will present with really high blood pressures. And the reason for that is that when you're having a stroke, that's part of the body's natural compensatory mechanism to deal with the stroke that you're having, is to increase the blood pressure to help with perfusion to the brain. Dr. Khyati Patel 07:48 And the other thing is, you know, you're looking for no bleeding anywhere else too. While these drugs are given IV, they go everywhere in the body. So while we're treating that stroke in the brain, they can also have effect elsewhere, if the body elsewhere is experiencing bleeding. And that goes without saying. You know, they can't be using anticoagulants concurrently. So we're talking Warfarin or doac, etc. Dr. Sean Kane 08:10 And that's probably the most common thing that comes up for pharmacy, is as soon as that patient comes in with a potential stroke, we do have to do a med history to understand if they're on a doac or Warfarin or Lovenox or something like that. So if they're on any of those with warfarin, if the INR is more than 1.7 then they don't qualify for a TPA. The caveat to that, though, is that if they're on aspirin, they can get TPA, and if they're on a prophylactic dose of something like VT prophylaxis, so we're talking like 40 milligrams of Lovenox. They are not excluded. They can still get TPA. So it's not even the drug, but actually the dose and the indication potentially dictate whether you can get TPA or not. Dr. Khyati Patel 08:53 Yeah, so kind of again, summarizing the use of exclusion and inclusion criteria is that patient should meet the inclusion criteria and not have any of the exclusion criteria we just discussed in order to get the TPA. Dr. Sean Kane 09:07 And I hope the audience appreciates that we're massively abbreviating the checklist. It's actually a checklist that all hospitals will have. There's a bunch more stuff that we're not going through that are more niche things. So we're covering kind of the highlights of that checklist, right? Dr. Khyati Patel 09:22 And the idea, even though we talked about that 4.5 hour, three hour window, the idea is to give the TPA as soon as possible again. Time is brain. There's some retrospective registry data evidence saying that the sooner you administer TPA, there is more benefit for the long term recovery. Dr. Sean Kane 09:40 And actually, in the hospital setting, it's very common that we will actually measure all of the things from the time the patient arrives to the hospital to the time they get TPA. So we're thinking, how long did it take to get the head CT? How long did it take to put in the order for TPA? Once the TPA order is put in, how long did it take to actually administer to the patient? All of these things are things that hospitals are trying really hard to optimize, because we know the sooner we do all of those things, the better it is for the patient. Dr. Khyati Patel 10:08 And then again, breaking down the available TPA option. So you know, talking about the king or the old agent, is the alteplase, the activase. This was kind of proven true from the NI NDS 1995 trial that improved neurological functional outcome in the acute ischemic stroke patients again. So you look at the the symptomatic improvement in the acute situation, so 24 hours, but then you also look at functional improvement in, you know, later on. So like, how are patients doing three to six months after when they had the stroke event, when they got the alteplase. So again, the with the alteplase, the benefit was not seen within shorter period of time, but at three months and six months, there was benefit seen. We did not see any mortality benefit. But that's what we had to use for the longest period of time until Dr. Sean Kane 10:59 tenecteplase, or TNK ace. So just like alteplase, tenecteplase is based on recombinant DNA technology, so it's based on human TPA. So when someone says TPA, they're they're referring to alteplase, because alteplase is truly the same amino acid sequence as TPA. The difference, though, is with tenecteplase, they change three amino acids. And it doesn't sound like that would be that big of a deal, but it actually really is a big deal. The big thing is that you get a longer half life, so that obviously determines how we dose it. But we're talking a half life of tenecteplase between 90 and 130 minutes, versus alteplase five minutes. So a massive increase in the half life with that three amino acid change. And then the other benefit is more of a theoretical benefit, that there may be better fibrin specificity to the activity in terms of that plasmid activity that we get, or in other words, by making this change. The thought is that tenecteplase may be more active in areas that you have clot, like the clot in your brain, and less active in areas that you don't have a clot, like in your stomach. Therefore, maybe the risk of GI bleeding could be lower because it's not working as much in your stomach and working more in your brain, where you have that clot. Yeah. Dr. Khyati Patel 12:14 So these structural differences, and you know, how how it behaves, how does that translate to how you apply that information in clinical practice? Dr. Sean Kane 12:24 Well, for sure, the biggest difference, Dr. Patel is how you actually give it to the patient. And this is going to be the main reason why many hospitals would choose to switch to tenecteplase. And I think probably the easiest way to talk about this is to walk through the process of actually giving alteplase to a patient and appreciating the complexity of it, right? So let's say you have that stroke patient. They have a negative head CT, you've they have all the inclusion criteria, none of the exclusion criteria. The decision is made. Let's give them alteplase. Great. So what you're going to do is that you're going to get a box that has a diluent and the powder in it, and there's a spike, and you basically shove a spike into both of the bottles, and then you use that to mix the product together. You swirl it, you don't shake it, because if you do that, it'll start foaming up. And it takes probably a couple minutes for everything to get into one vial, for it to fully dissolve, to get to the point where you're ready to go. At that point, though, you have to do some math, and the dosing is this classic thing that everyone has to memorize in pharmacy school. So it's 0.9 milligrams per kilogram, and you give 10% as a bolus, 90% as a one hour infusion, and the total max dose is 90 milligrams. So it's not complex math, but it's enough math that, like you can't just do it off the top of your head without double checking, right? So there's a little bit to it. Now, the wrinkle is, so the max dose is 90 milligrams, but it's a 100 milligram vial, so you're guaranteed to not use at least 10 milligrams or even more. And if you think about it, a really bad scenario would be that you give that extra to the patient, right? Like you don't want to do that. So for safety reasons, we remove whatever we're not going to give to the patient. So let's say that we had an 89 kilogram patient, their dose would be 80 milligrams. So 80 milligrams is their total dose. We're going to take 20 out of the vial, because it's 100 milligram vial. So now we're left with 80 milligrams of that. 88 milligrams or 10% is going to be their bolus dose. So we'll literally take a syringe and a needle, shove it into the vial, pull out our eight milligrams, and then we'll give that as an IV push. And then what we do is that we spike the vial that has the remaining dose in it with IV tubing. We connect it to an IV pump. We configure the IV pump, we hang that over one hour, and at the end of that one hour, we still have a bunch of TPA left in that tubing. It could be 10 to 20 MLS, which is actually a lot, right? So then at the end of the infusion, you have to chase that TPA with normal saline at the same. Rate that you were infusing the TPA in so that you can ensure the patient got the full dose. So from beginning to end, you're doing a bunch of math. You're putting things into this vial, spiking it, using needles, withdrawing stuff, giving boluses. There's a lot of like logistics in terms of not messing this up. And it's a really expensive drug, and if you do mess it up, you have to get a new one right. So ideally you want to do it right the first time, both for patient safety reasons, but also for cost reasons. Dr. Khyati Patel 15:27 And I think this drives the importance of having pharmacists on the stroke code teams, you know, working with the nursing staff and making sure the IV is running Okay, the math is happening properly, the patient's getting the right rate and whatnot. So that's a great example. How does tenecteplase make our life easy? Dr. Sean Kane 15:46 And it's so much easier. Okay, so with tenecteplase, you have a vial with a powder and a diluent, just like you had with alteplase. You do have to do math. The math here is 0.25 milligrams per kilogram with a max dose of 25 milligrams. So for that 89 kilogram patient, it's 22.3 milligrams. So the vial comes as 50 milligrams, and you give whatever the dose is for the patient as an IV injection, so an IV push, so no IV tubing, no configuring an IV pump. Really, you don't have to waste any of that vial, because you're handing the nurse a syringe, and then the nurse injects it, and you're done. So that is massively easier from a calculation standpoint, from a logistic standpoint of not chasing it with some normal saline and stuff like that, it's in the patient within five seconds, and you're done, and that's it. Dr. Khyati Patel 16:37 Yeah. And then if they're giving it through the IV line, just flush it with a little bit of normal saline and you're good to go much easier. Dr. Sean Kane 16:43 Yeah. So really, the question would be like, why would you not do that? Right? Like, that seems so easy. The classic example is, well, alteplase is FDA approved for stroke, but tenecteplase is not. It still does not have that indication, despite having 1000s of patients that have received tenecteplase for stroke, which is really interesting. So you're Dr. Khyati Patel 17:04 saying we have evidence from clinical trials, but FDA is just taking its sweet time for Dr. Sean Kane 17:08 approving it, or the drug manufacturer doesn't feel like they need to, because they have enough phase three trial data that they don't need to spend a bunch of money for that to happen. And probably the best example of that is if you look at the 2019 acute stroke guidelines, they have a recommendation that says, quote, it may be reasonable to choose to neck the place over alteplase. This is a class of recommendation to be level of evidence. Br, which means that we have randomized trials supporting this, and it's kind of a lukewarm might be reasonable type recommendation. So even the stroke guidelines say, if you were to pick one, maybe there's a little bit of evidence favoring tenecteplase overall to place, but it's still kind of a lower strength of recommendation. Dr. Khyati Patel 17:48 So let's dive into that particular randomized control trial that this recommendation is stemming from. Believe that one's the EXTEND-IA TNK study, and we have the show notes in the link. Dr. Kane just summarizing this. You know how many patients were included, what was the primary endpoint and what were the results? Dr. Sean Kane 18:06 So this is the trial that is most commonly cited, because it's the one that shows all tenecteplase might be better, and in a minute, we'll talk about other data that says maybe this isn't the case, but this is the one that people get excited about. So this was a roughly 200 patient trial, and they included a very specific patient population here. These are patients who were eligible for what's called mechanical thrombectomy, which we'll talk about in a second, but it's literally that they go in and suck out the clot from the brain, but we only do that in patients that have what's called an anterior circulation occlusion of a large cerebral artery. So this is probably like 10% of stroke patients ish. So this is not your typical stroke patient population that we're looking at. All of these patients had symptom onset within four and a half hours. So remember, this is like the more or less typical timeframe for giving TPA, and they randomized patients to tenecteplase or alteplase at the doses that we've talked about. So all of these patients had a planned visit to have mechanical thrombectomy. So everyone got TPA, and then they put them in an interventional radiology suite. They gave them contrast to figure out where the clot was, and their plan was to suck that clot out. And we'll talk about the technology in a second. So the primary endpoint was before they did the mechanical thrombectomy. So before they sucked the clot out, after they've given TPA, did they see that at least 50% blood flow was restored to wherever that clot was at? So you could think of it as is at least half the clot gone, or more, or could they not even see the clot? And they didn't need to do mechanical thrombectomy. So this is kind of a kind of a surrogate marker, right? Because we're not looking at mortality or functional status. We're just looking at when you look at that blood vessel, is most of the clot gone or not sure? And what did they find? So 22% of the time with tenecteplase, the clot was mostly gone, and only 10% of the time with alteplase, the clot was mostly gone and it was. Designed as a non inferiority trial, and it met non inferiority. And it actually also met superiority, almost by accident. It wasn't powered for that, but that's what they they showed. I do kind of want to highlight, you know, 22% of patients having most of the thrombus gone. That's that's really not that good. That means 78% of the time there's still a lot of clot left in that cerebral artery that was eligible to be removed through mechanical thrombectomy. Yeah. Dr. Khyati Patel 20:26 So the primary outcome was looking at shorter term data, surrogate marker, as we talked about, but it looks like they also followed up with patients after 90 days and looked at quote, unquote, long term data. What were some of those results? Were they significantly different? Dr. Sean Kane 20:40 And this is really the classic endpoint that we'd like to see with almost all stroke trials, which is the neurologic or the functional outcome of our patients longer term. So at least 30 days, 90 days is even better. And what they found was patients that received tenecteplase had a more favorable functional outcome on what's called a modified Rankin Scale. And the odds ratio was 1.7 so you can almost think of it as like you were 1.7 times more likely to have a better functional outcome. That was significant, and the median in the trial for that modified Rankin Scale was two with tenecteplase versus three with alteplase. The higher number is worse. And really that difference is, if you're a two, you have a slight disability, so you live independently, but you can't do everything that you used to do. And a three is that you can still walk, but you require assistance with some activities of daily living. So that, I would argue, is a different functional outcome between A two and A three that would be meaningful for most patients. And I Dr. Khyati Patel 21:36 believe they also looked at the 90 day independence function. Again, this was modified ranking scale of zero to two, so less than two and three that we discussed earlier. And this was not statistically significant between tenecteplase and alteplase, Dr. Sean Kane 21:51 and it was close. And again, this was designed as a non inferiority trial, so you could definitely argue it wasn't powered to even look at these things, but we're still going to look at them anyway. They also looked at early neurologic improvement, so within 72 hours, based on the NIHSS score, and there was no difference. But again, almost paradoxically, even in that really early 1995 trial, you would expect to see a benefit early on. So the way that these clot busters work, they have really short half lives, that clot is either going to be gone or not gone pretty quickly, based on the half life of the drug, you would expect to see a difference. But we did not see it in that NINDS 1995 trial, and we also did not see any difference here in this trial at 72 hours. So for whatever reason, even though the duration of effect is really short with our TPA and tenecteplase, the benefit that you observe actually takes a long time to actually observe that benefit. Dr. Khyati Patel 22:44 Yeah, it makes sense based on the primary outcome as well as you know, those 90 day outcomes that we just discussed, those are efficacy outcomes. What about safety? Comparing bleed risk, you know, other other events, yeah. Dr. Sean Kane 22:56 So kind of interestingly, they report death as a safety event, which, I guess that makes sense, but you could also argue it's an efficacy event. So tenecteplase had lower mortality here. So it was 10% versus 18% with alteplase a relative risk of point five. It was technically not significant based on the confidence interval, but the p value was basically at point 05 they also looked at symptomatic intracranial hemorrhage, which is our classic safety endpoint for stroke trials using thrombolytics, and it was 1% both groups, no difference. And then they also looked at any head bleed, whether it was symptomatic or not that caused brain tissue to move over, called a Mass Effect. And it was 6% with tenecteplase versus 5% with alteplase, and no difference with that P value. Dr. Khyati Patel 23:39 All right, so this is one trial, Dr. Kane, we broke down that showed some benefit of tenecteplase overall to place. But I can't believe this is the only trial, right? There's probably been other comparison done in other patient population, yeah. Dr. Sean Kane 23:52 So this is the trial that, if you like tenecteplase, this is one you talk about, and you don't talk about the meta analysis that we also have linked in our show notes. And there's actually several meta analyzes out there. I just picked one of the more recent ones. This was nine randomized, controlled trials with almost 4000 patients with stroke. And basically, the long story short is there are similar outcomes, definitely not worse outcomes with tenecteplase. They're similar both in terms of 90 day neurologic functional outcomes, symptomatic intracranial hemorrhage outcomes, mortality outcomes, it would appear that the trial that we just talked about, the extend, IA, T and K trial, is more of an outlier in terms of showing benefit with tenecteplase most of the data. And when you pool all of the data, it would appear that tenecteplase is probably just as good from an efficacy and a safety standpoint. Dr. Khyati Patel 24:42 So really, the recommendation that the guidelines have put together, perhaps sides with that one study, but also more sides with the difficulty of administering, you know, alteplase versus the ease of administering to an active place, easier for nurses, easier for the pharmacy teams. And perhaps it's the right recommendation. Patient in place? Dr. Sean Kane 25:00 Yeah. And I think on top of that, we probably don't have that big trial showing a true comparison among all stroke patients. It's like many 1000s of patients, really. The biggest trial in that meta analysis was about 1000 which sounds like a lot, but to be able to see a functional outcome in a stroke patient population, you probably do need a lot of patients for this particular intervention to change how how functional they are at you know, 90 days down the road, you do need a lot of patients for that. That makes sense. Dr. Khyati Patel 25:31 We talked a little bit earlier, Dr. Kane about mechanical thrombectomy, and I think that's one of the interventions that we use in acute ischemic stroke patient. Let's talk a little bit about that. You know what it is, and when do we consider it? Dr. Sean Kane 25:43 And Dr. Patel, this is, as pharmacists, we probably don't talk about this enough, but this is one of the more exciting areas of stroke management, and the reason is that it seems like it's a fairly safe intervention and has pretty profound efficacy in terms of helping patients with longer term functional outcomes. So basically, what we're talking about here is among selected patients. It's not for all stroke patients, but selected patients, you can thread a catheter all the way up into the brain through, typically, the femoral artery, find where the clot is, and you can either suck out the clot, called aspiration like a vacuum cleaner, almost, or more commonly, they do what's called a stent retriever. And it's not the same thing as like a cardiac stent. What they're actually doing is that they have this mesh that they push through the clot, expand it, and it gets stuck into the clot, and that allows them to pull the clot all the way from, let's say, your middle cerebral artery, all the way down to your leg in the femoral artery and pull it out of your body that way. Dr. Khyati Patel 26:44 That is so cool. Yeah. Dr. Sean Kane 26:48 And as I mentioned, it's not for everyone. So the main thing is that you have to have a large arterial occlusion, which means, typically, these patients are having special imaging done to show where the stroke is happening, with a normal CT scan of the head, you typically don't see that, so you have to have special imaging. It has to be the anterior circulation of the brain. It doesn't mean the posterior circulation can't be done. There's just not enough data for that. So most of the trials look at certain blood vessels in the front half of the brain, as opposed to the back, and then the stroke onset. This is probably the most exciting part, is within 24 hours. So I just want to emphasize that with giving thrombolytics, it's between three and four and a half hours of last known normal time for these patients, it's 24 hours. So there's a ton of patients that wake up with stroke symptoms, but they went to bed 12 hours ago. They're not indicated for TPA, but they could be indicated for this mechanical thrombectomy procedure. There's a bunch of other inclusion criteria that we're not going to talk about, but sure, that's what's really exciting, is it extends the window of an intervention that you can give to these patients with very disabling strokes, Dr. Khyati Patel 27:56 and so the time becomes more of a siting factor with these patients, right? Instead of excluding factor, would these patients still get T PA? Dr. Sean Kane 28:06 Yes, and that's like one of the crazy things. So normally, when you get T PA for the next day, you can't even have aspirin, like, no one's gonna do a surgical procedure on you. They'll still put in IV, like peripheral IVs. But nobody wants to cut those patients any shape or form, right? But the typical scenario here is that, if they're indicated, they will get TPA and they will go for mechanical thrombectomy. And just remember, they're cannulating These patients through their femoral artery. Arteries have high pressure. They like to bleed. We don't want to do any procedure in people who get TPA, but we will do it because the benefits outweigh the risk. In terms of doing this procedure improves functional outcomes at the risk of a slightly increased bleeding risk and where they cannulate the patient. Dr. Khyati Patel 28:48 Well, that's really neat to know. In addition to just knowing the ins and outs of the TPA, circling back to our TPAs, we discussed, you know, just pharmacokinetic differences, administration differences. We discuss the efficacy and safety differences. Can we talk about cost differences? Why would a hospital want to keep one over the other? Dr. Sean Kane 29:08 And this is probably the number two reason, aside from convenience, why many hospital systems are switching to 10 active place? You know, we can't share, like, what our hospital system pays for these two products, but we can share the Red Book a WP. And a WP is always inflated, so this is not the actual cost, but it's a way to compare apples to apples. So with tenecteplase for one vial 100 milligrams, the cost is about $10,000 and I can tell you it's probably closer to half that in terms of what a typical system may pay. But the AWP for tenecteplase is about $9,000 so we're looking at a 10 to 20% difference in terms of the AWP cost. So if you consider it is cheaper for most hospital systems and it's more convenient, less prone to drug errors, that's why many institutions are switching over to tenecteplase. Dr. Khyati Patel 30:00 Place, and that probably makes sense. Doctor Kay we earlier talked about the efficacy and safety issues with TPA from the clinical trials and intracranial hemorrhage was mentioned as one. But if we can summarize just risk associated with TPA, probably this is included in the consent form that either the patient or the family is signing off on before they receive it, we noted that from that 1995 trial, the rate of symptomatic intracranial hemorrhage was 6.4% with alteplase versus point 6% with placebo. This is number needed to harm 17% but again, we can argue the reason we are giving it because the benefit outweighs the risk. Dr. Sean Kane 30:40 Yeah, and the good news is that with more modern data, so anytime we've studied it, not 1995 the rate of symptomatic intracranial hemorrhage is way better, way lower than that 6.4% we saw in the NINDS trial. So if you look at that meta analysis that we linked, the risk was about 3% with alteplase or tenecteplase, so half of what we saw in the NINDS trial and different articles go down maybe even to 1% risk. So certainly the risk is lower than it used to be, either because of better patient management, better recognition that this is a potential adverse event, whatever it is, the risk is lower than it used to be, but still certainly a pretty feared risk, because if a patient does have a symptomatic intracranial hemorrhage, their outcomes are really bad compared to someone who doesn't have Dr. Khyati Patel 31:30 that right? And I'm sure the management systems and you know, steps are put in place that the patient does end up getting an ich so therapies like aminocaproic acid or tranexamic acid or cryoprecipitate are used to contain the bleed further. Dr. Sean Kane 31:45 Yep, and obviously, with alteplase, because it's a 60 minute infusion, if they started bleeding while the infusion is happening, which would be somewhat unusual, you at least have the benefit of stopping the infusion. But with tenecteplase, it's in, so once it's in, you have this long half life. You're kind of married to it, which is why you might be more excited. To give amicar or TxA, because it inhibits that fibrinolysis. But really, all of these therapies haven't been proven. They're all theoretical in terms of their mechanism. Seems like a good idea to reverse the effects of TPA, Dr. Khyati Patel 32:17 and in addition to ich and intracranial hemorrhage, angioedema tends to occur with these agents. Dr. Sean Kane 32:23 Yeah, this. I feel like this is one of those, like, sleeper side effects that nobody really appreciates until they see a patient that had it. And then you look at the package insert, it's like, totally a thing. So we're looking at a 0.5 to 1% incidence rate of angioedema with mostly with alteplase. But of the data we have, it doesn't appear that tenecteplase has any different risk of it. So it seems like they're fairly similar. And basically, obviously, if they're getting alteplase, you stop the alteplase. But again, with tenecteplase, it's already in the management is just like Ace induced angioedema. There isn't really a therapy aside from stopping the therapy that gave them the angioedema. We still give them steroids, we still give them h1 blockers like Benadryl, we still give them h2 blockers like famotidine, because we feel better about ourselves in doing that. But there's no data that says any of those therapies work. It's probably just time to get rid of the causative agent and then have the body kind of relax a little bit and get rid of that angioedema. Dr. Khyati Patel 33:19 Yeah, so usual management that we pursue for Andrew edema is what we would do here, exactly. Dr. Sean Kane 33:25 Well, Dr. Patel, I think that wraps up today's episode quite nicely. You know, some of the big takeaway points for me are, we have two commonly used thrombolytics for acute ischemic stroke. We have alteplase or activase. This is basically the same TPA in your body, just a recombinant DNA version, and then we have tenecteplase, or T and K ace, which is similar, but has three different amino acids that give it longer half life and a higher fibrin specificity. Dr. Khyati Patel 33:51 And again, in patients with stroke, alteplase is given as a bolus, and we have to follow it by a 60 minute infusion. So that's the difference in administration versus but tenecteplase, we give it as IV bolus. There is no need for additional infusion thereafter Dr. Sean Kane 34:08 and then in terms of efficacy and safety, based on the data, if you take everything together, tenecteplase seems to be at least as safe and effective as alteplase for acute ischemic stroke. There are some studies, like the one that we mentioned, that is linked in the show notes, it did show more benefit, which is where the guidelines get a little bit excited about maybe favoring tenecteplase. But on the whole, with the data we have, it would appear that it's pretty balanced in terms of safety and efficacy between the two therapies. Dr. Khyati Patel 34:35 And last but not the least, in a small subset of patient who are eligible for mechanical thrombectomy, we can still give the thrombolytics, the alteplase or tenecteplase, but again, we have to make sure that these patients meet the inclusion criteria, and they don't have any of those exclusion criterias. Perfect. Dr. Sean Kane 34:53 Again, this was a listener requested topic, so if you would love us to review a topic that's kind of hot in your world of you. Pharmacy or even healthcare in general, please reach out to us at HelixTalk.com we love the five star reviews and iTunes, and we also have a mailing list that you can sign up on our website, HelixTalk.com so whenever we release these new episodes, you can get an email that kind of summarizes the episode and lets you know that that new episode is live and available for you to enjoy. So with that, I'm Dr. Kane Dr. Khyati Patel 35:20 and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 35:24 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 - ? 35:35 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.