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NINDS Trial Explained Stroke Thrombolysis Risks and Benefits · This Is Why with Dr. Busti

• 0:00
  SPEAKER_00: Okay, guys, we got a 65-year-old male patient arriving by EMS with a report of one hour and 15 minutes from sudden onset of aphasia and right-sided upper and lower extremity weakness.
• 0:14
  SPEAKER_00: Okay, the point of care glucose, 123 milligrams per deciliter.
• 0:20
  SPEAKER_00: Initial blood pressure, 178 over 97.
• 0:24
  SPEAKER_00: Stat CT scan shows no hemorrhage.
• 0:29
  SPEAKER_00: The concerned wife looks at you and the team and asks the question that we've all heard at some time or in some form: what can we do?
• 0:39
  SPEAKER_00: Please help my husband.
• 1:06
  SPEAKER_00: In this series on landmark clinical trials, we're going to explore practice-changing studies within the context of the broader evidence so that we can better understand how and why these types of clinical trials apply in real-world practice.
• 1:24
  SPEAKER_00: This isn't meant to be, though, an exhaustive journal club.
• 1:28
  SPEAKER_00: I do want to say that up front.
• 1:29
  SPEAKER_00: Instead, our goal is to distill each study to its essentials and place it in the proper context so that we can better understand why we do what we do, not just memorizing a bunch of data from a study.
• 1:52
  SPEAKER_00: That was published in the New England Journal of Medicine 1995.
• 1:57
  SPEAKER_00: And this is one of those trials where the results are not only important, but the way you and myself explain the results is just as critical.
• 2:10
  SPEAKER_00: Because the message is not TPA is harmless, it's not every patient who has a stroke should get thrombolysis, and it's not the drug clearly saves lives.
• 2:23
  SPEAKER_00: The message is more precise, isn't it?
• 2:26
  SPEAKER_00: In carefully selected patients with acute ischemic stroke treated very early, within three hours in this trial, altoplace increased the chance of meaningful functional recovery despite increasing the risk of symptomatic intracerebral hemorrhage.
• 2:46
  SPEAKER_00: Okay, so the question becomes, guys, why was that enough to change practice?
• 2:53
  SPEAKER_00: Well, before the NINS trial, acute ischemic stroke was largely a disease we diagnosed, supported, and watched.
• 3:02
  SPEAKER_00: We managed the blood pressure, airway, glucose, complications, and rehab, but we did not have a clear proven therapy that directly reduced neurologic injuries and disabilities.
• 3:17
  SPEAKER_00: That's the rationale for thrombolysis, was therefore biologically attractive, very similar to cases like we see in ST segment elevation MI.
• 3:29
  SPEAKER_00: Okay, with an artery is blocked by clot or atheroscrotic plaque, and brain tissue is not fully, is not yet fully infarcted, early reperfusion might salvage that tissue.
• 3:44
  SPEAKER_00: But the problem was equally obvious.
• 3:46
  SPEAKER_00: Lysine clot in a recently infarcted brain can cause hemorrhage due to the weakening and the breakdown of tissue.
• 3:55
  SPEAKER_00: That's obvious.
• 3:57
  SPEAKER_00: So early thrombolytic trials had made clinicians appropriately cautious about intracerebral hemorrhage.
• 4:04
  SPEAKER_00: Was not only real, but was also a potential major complication.
• 4:09
  SPEAKER_00: So think about it this way, guys.
• 4:12
  SPEAKER_00: We in the field and in healthcare did not need a drug that just made the CT scan look better, right?
• 4:20
  SPEAKER_00: We needed a drug that made the patient more likely to walk, speak, feed themselves, and live with less disability.
• 4:31
  SPEAKER_00: Okay?
• 4:31
  SPEAKER_00: And that was the clinic a clinically meaningful question that we were asking or that the study was asking for of itself.
• 4:39
  SPEAKER_00: So the NINS investigators designed a randomized, double-blind, placebo controlled trial in two parts.
• 4:48
  SPEAKER_00: Okay, two parts.
• 4:50
  SPEAKER_00: The patient had to have a clear time of onset, a measurable objective neurologic deficit, and a CT scan showing no intracranial hemorrhage.
• 5:05
  SPEAKER_00: Now they excluded many patients that we still actually care and worry about today, and you're going to see them.
• 5:14
  SPEAKER_00: Those with very high blood pressure, recent major bleeding, recent major surgeries, those are using certain types of anticoagulation or abnormal coagulation parameters, thombocytopenia, extreme glucose values, right?
• 5:32
  SPEAKER_00: Rapidly improving symptoms and even minor symptoms.
• 5:37
  SPEAKER_00: So what do they do?
• 5:39
  SPEAKER_00: You had that clear definition of who they were looking for and who they kind of said, yeah, it's probably too risky, right?
• 5:47
  SPEAKER_00: They had to make a decision.
• 5:48
  SPEAKER_00: And they chose intervention.
• 5:50
  SPEAKER_00: So the intervention was all to place at 0.9 milligram per kilogram with a maximum dose of 90 milligrams.
• 5:59
  SPEAKER_00: Now, 10% of that was given as a bolus, and the remaining was infused over a period of 60 minutes.
• 6:08
  SPEAKER_00: Okay.
• 6:09
  SPEAKER_00: Now patients were treated within three hours, remember, of onset of those symptoms.
• 6:14
  SPEAKER_00: Okay, and the trial stratified them by 0 to 90 minutes, and those at 91 to 180 minutes.
• 6:22
  SPEAKER_00: And they did that in part to see if there was differences in results.
• 6:26
  SPEAKER_00: Okay, obviously.
• 6:28
  SPEAKER_00: So antiplatelet and anticoagulant therapy was held for 24 hours, and blood pressure was largely managed very carefully.
• 6:37
  SPEAKER_00: Now, one of the things I want you guys to notice is that part one did not meet its primary endpoint.
• 6:47
  SPEAKER_00: Okay.
• 6:48
  SPEAKER_00: So what is that?
• 6:50
  SPEAKER_00: At 24 hours, neurologic improvement occurred in 47% of patients who were treated with altoplase or TPA versus 39% of those treated and given placebo.
• 7:05
  SPEAKER_00: Now, that sounds like a directionally favorable difference, doesn't it?
• 7:12
  SPEAKER_00: But it was not unfortunately statistically significant.
• 7:16
  SPEAKER_00: The p-value was 0.21.
• 7:20
  SPEAKER_00: Okay.
• 7:22
  SPEAKER_00: So what does that mean?
• 7:23
  SPEAKER_00: How do you take that p-value and interpret its its the value of what it represents, right?
• 7:30
  SPEAKER_00: So the p-value would suggest that there's 21% chance that the results from this study were due to random error or by chance alone.
• 7:39
  SPEAKER_00: So remember the p-value is really about how true is the null hypothesis.
• 7:47
  SPEAKER_00: Now I do a lecture on what a p-value is and isn't in our EBM series.
• 7:52
  SPEAKER_00: So we have different playlists and different categories of lectures.
• 7:56
  SPEAKER_00: And if you want to learn more about that and p-values as well as confidence intervals, right, head over that way and check those out.
• 8:04
  SPEAKER_00: But remember, p-values do not determine clinical relevance or significance.
• 8:10
  SPEAKER_00: Now, so here's another nuance that we need to teach.
• 8:15
  SPEAKER_00: When we fail to find a difference, like in part one, we need to ask ourselves: was it due to insufficient sample size or power to find that difference?
• 8:25
  SPEAKER_00: Right?
• 8:26
  SPEAKER_00: Because we don't want to make a type two error.
• 8:28
  SPEAKER_00: Well, part one was actually powered to detect a fairly large and early difference.
• 8:37
  SPEAKER_00: Okay?
• 8:39
  SPEAKER_00: A 24% point absolute difference in 24 hours of improvement endpoint, assuming a 16% placebo response rate with a power of 90% and an alpha of 0.05 that was two-sided.
• 8:57
  SPEAKER_00: And that's pretty pretty good.
• 8:59
  SPEAKER_00: Okay.
• 9:00
  SPEAKER_00: Now again, we cover topics like power analysis, alpha in our EBM series.
• 9:07
  SPEAKER_00: You're welcome to go over there.
• 9:09
  SPEAKER_00: Okay, but this was a pretty robust design, really trying to avoid making a type 1 error.
• 9:16
  SPEAKER_00: Okay?
• 9:17
  SPEAKER_00: But the question still remains: did they still make a type 2 error?
• 9:20
  SPEAKER_00: Okay.
• 9:21
  SPEAKER_00: That's still there.
• 9:23
  SPEAKER_00: Alright, so the actual observed difference was about 8 percentage points.
• 9:28
  SPEAKER_00: So the trial did not prove that TPA had no early effect.
• 9:35
  SPEAKER_00: It just failed to demonstrate that the pre-specified early endpoint, okay, part one, uh, and that it may have been underpowered to detect a smaller, earlier effect.
• 9:47
  SPEAKER_00: Okay.
• 9:48
  SPEAKER_00: So now the results of part one endpoint is that the risk of a potential type two error, but there's also another layer to this.
• 9:58
  SPEAKER_00: Remember, the endpoint itself was dichotomized.
• 10:02
  SPEAKER_00: All right, well, what do I mean by that?
• 10:04
  SPEAKER_00: Well, it was either complete resolution or at least a four-point in the NIH stroke scale at 24 hours.
• 10:15
  SPEAKER_00: All right, now later discussions and reviews of this trial pointed out that that four-point early improvement definition had limited prospective validation and may not have been the most sensitive way to detect early neurologic change.
• 10:35
  SPEAKER_00: And so when we teach about part one, we should not say there's no early signal.
• 10:43
  SPEAKER_00: We should say the pre-specified 24-hour binary endpoint was negative, but that endpoint may have been insensitive to smaller or differently measured earlier improvements.
• 10:58
  SPEAKER_00: Okay.
• 10:58
  SPEAKER_00: So remember the guys, this is so important why in a study design, okay, if you think about statistical analysis plans or SAPs that we cover in our EBM lectures, is so important how you define the endpoints, what they are, the criteria for your alpha and your power analysis really do drive some of this.
• 11:18
  SPEAKER_00: Okay, again, research is hard, very difficult sometimes to do, and not always ideal or perfect like we want them to be.
• 11:27
  SPEAKER_00: All right, now let's move on to part two.
• 11:30
  SPEAKER_00: Okay, now this is where we asked more patient-centered questions.
• 11:34
  SPEAKER_00: What is the patient's functional outcome at three months?
• 11:38
  SPEAKER_00: Okay, and that's where the trial changed the field.
• 11:42
  SPEAKER_00: Okay, so in part two, the overall global odds ratio for a favorable three-month outcome was 1.7, with a 95% confidence interval of 1.2 to 2.6.
• 12:00
  SPEAKER_00: Okay.
• 12:01
  SPEAKER_00: Now, if you look at the individual scales that they used to measure some of this, the results consistently favored Altiplace.
• 12:10
  SPEAKER_00: Okay, that's like modified rank and scale of 0 to 1 occurred in 39% with altiplace versus 26% with placebo.
• 12:21
  SPEAKER_00: Barthol index favorable outcome occurred in 50% in altiplace versus 38%.
• 12:27
  SPEAKER_00: The NIH stroke scale of 0 to 1 occurred in 31% of Altiplace versus 20% in the placebo.
• 12:36
  SPEAKER_00: Okay, so the investigators summarized this at the that there is at least a 30% greater likelihood of minimal or no disability at three months with an absolute increase in favorable outcome of about 11 to 13 percentage points.
• 12:59
  SPEAKER_00: Okay, so here's why that mattered.
• 13:02
  SPEAKER_00: The drug did not primarily demonstrate a mortality benefit.
• 13:07
  SPEAKER_00: 90-day mortality was 17% with altoplase and 21% with placebo, but remember it wasn't statistically significant.
• 13:15
  SPEAKER_00: The outcome that moved the field was a reduction in disability.
• 13:21
  SPEAKER_00: Okay, so at the bedside, I would not say things like, you know, this drug saves your life.
• 13:28
  SPEAKER_00: I would say instead, this treatment may improve the chance of recovering with little or no disability, but it also does increase the risk of bleeding in the brain, and that bleeding can be unfortunately fatal.
• 13:45
  SPEAKER_00: Now let's make the numbers clinically relevant and practical.
• 13:49
  SPEAKER_00: Okay, so going back to part two, using that modified rank and scale, there were the results were 39% for altoplase versus 26% for placebo.
• 14:01
  SPEAKER_00: So the absolute benefit is 13%.
• 14:05
  SPEAKER_00: It's just taking the difference between those.
• 14:07
  SPEAKER_00: Now you need that absolute difference in order to calculate and determine the number needed to treat, NNT.
• 14:16
  SPEAKER_00: Remember, you so you take one divided by that difference, so one divided by 0.13 or 13%, right, is about 7.7.
• 14:28
  SPEAKER_00: We typically round up because it's just easier to describe, especially to patients and other clinicians.
• 14:34
  SPEAKER_00: So about eight.
• 14:35
  SPEAKER_00: Okay, so in other words, we have to treat about eight patients with similar presentations in the clinical trial context so that one of those patients has a favorable functional outcome on one of those scales at three months.
• 14:52
  SPEAKER_00: That's what it means.
• 14:54
  SPEAKER_00: That's how you interpret that information to a person or to your own colleagues, or when we're teaching our residents and students, right?
• 15:02
  SPEAKER_00: Now, if you use the other outcome scales, the absolute benefit is still roughly around 11 to 13 percent.
• 15:08
  SPEAKER_00: So the number needed to treat, again, ranges eight to ten.
• 15:13
  SPEAKER_00: Okay.
• 15:14
  SPEAKER_00: But now we have to consider the harm.
• 15:17
  SPEAKER_00: Okay, I mentioned that in that comment that I would say to the patient, with the same degree of clarity as the benefit.
• 15:25
  SPEAKER_00: Because you can't just look at one by itself.
• 15:28
  SPEAKER_00: Now, symptomatic intracerebral hemorrhage within 36 hours occurred in 6.4% of patients receiving altoplase versus 0.6% in placebo.
• 15:47
  SPEAKER_00: So what is the absolute increase?
• 15:50
  SPEAKER_00: Well, it's about 5.8%.
• 15:53
  SPEAKER_00: All you do is take the difference between 6.4% minus 0.6%, and you get 5.8%.
• 16:01
  SPEAKER_00: Again, that's the absolute difference.
• 16:04
  SPEAKER_00: So we do the, now we do 1 divided by that.
• 16:07
  SPEAKER_00: So 1 divided by 0.058, because you convert the percentage to the number, and you get a number needed to harm NNH of about 17 to 18.
• 16:20
  SPEAKER_00: Okay, that means that for every 17 to 18 patients that we treat based on the trial, okay, in that setting, there's going to be one of them that can develop a symptomatic intracerebral hemorrhage attributed to the infusion of TPA or altoplase.
• 16:41
  SPEAKER_00: Now, fatal intracerebral hemorrhages at 36 hours occurred in nine of 312 patients in the altoplase group versus one in the 312 patients placebo-treated group.
• 16:56
  SPEAKER_00: So that is about a 2.9% versus a 0.3% with an absolute increase of about 2.6%.
• 17:04
  SPEAKER_00: I mean it's just the difference again.
• 17:05
  SPEAKER_00: What's the number needed to treat for that?
• 17:07
  SPEAKER_00: For fatal.
• 17:08
  SPEAKER_00: The number number needed to harm, sorry.
• 17:11
  SPEAKER_00: NNH is 39.
• 17:12
  SPEAKER_00: So I have to treat 39 patients based on the trial criteria and give them multiplays for one of them to develop a fatal intercerebral hemorrhage.
• 17:23
  SPEAKER_00: Now, you might say, okay, well, is that is that too much?
• 17:27
  SPEAKER_00: Is that enough?
• 17:27
  SPEAKER_00: Or is that fine?
• 17:28
  SPEAKER_00: Or is that acceptable?
• 17:30
  SPEAKER_00: Again, you're trying to communicate data that's not perfect and making inference back to the general population as you communicate to either those that you're training, or if you're talking to the patient and their family in ways that they can understand it at some level.
• 17:48
  SPEAKER_00: Okay.
• 17:49
  SPEAKER_00: Now, minor external bleeding is also a different conversation, right?
• 17:53
  SPEAKER_00: That happens.
• 17:54
  SPEAKER_00: I mean, we're given a drug that makes people bleed, right?
• 17:56
  SPEAKER_00: Or it can increase the risk of bleeding.
• 17:58
  SPEAKER_00: It occurred in 23% of multiplace versus 3% of placebo, giving a number needed to harm of about five five.
• 18:07
  SPEAKER_00: Okay, so yes, not very high, small number, uh less desirable, but it's minor.
• 18:13
  SPEAKER_00: Okay.
• 18:14
  SPEAKER_00: But this is not the same as obviously the devastating fatal intracranial hemorrhage.
• 18:19
  SPEAKER_00: Okay.
• 18:20
  SPEAKER_00: So when we teach bleeding risk, we have to separate common minor bleeding from that serious systemic bleeding or symptomatic intracerebral hemorrhage or even fatal intracerebral hemorrhage.
• 18:34
  SPEAKER_00: Okay, that is the heart of the risk-benefit conversation.
• 18:40
  SPEAKER_00: Okay, so the number needed to treat of eight does not cancel out the number needed of harm of 18, okay, because those are different outcomes.
• 18:51
  SPEAKER_00: Both are important and relevant.
• 18:53
  SPEAKER_00: So one is improved functional recovery, the other is symptomatic brain bleeding.
• 18:59
  SPEAKER_00: Okay, now the right clinical move is not to compare them as equal weights.
• 19:04
  SPEAKER_00: I just need to stress that point.
• 19:06
  SPEAKER_00: So the right move is to explain both honestly and ask whether this patient who's sitting in front of you, right, matches the population where the net benefit is expected.
• 19:17
  SPEAKER_00: Well, the one-year follow-up held helped answer some of that important question.
• 19:23
  SPEAKER_00: What was that three-month benefit that they saw in part two durable?
• 19:28
  SPEAKER_00: It was, thankfully.
• 19:30
  SPEAKER_00: At six months and 12 months, the global statistic still favored altoplaser TPA with an odds ratio of 1.7 at both of those time points.
• 19:41
  SPEAKER_00: Okay, now at 12 months, altoplase treated patients remained at least 30% more likely to have minimal or no disability, with an absolute favorable outcome increase of 11 to 13 percentage points.
• 19:59
  SPEAKER_00: Okay?
• 20:00
  SPEAKER_00: Now mortality at 12 months was 24% in the altoplace group, 28% in the placebo group, okay, placebo group.
• 20:08
  SPEAKER_00: That's not statistically significant.
• 20:10
  SPEAKER_00: Okay, and recurrent strokes were also very similar, so there was no difference.
• 20:16
  SPEAKER_00: Okay.
• 20:16
  SPEAKER_00: Now let's pause on that odds ratio, because this is where learners can accidentally overstate the result.
• 20:24
  SPEAKER_00: Okay.
• 20:24
  SPEAKER_00: So, again, guys, my goal and intention of doing landmark clinical trials is not only just to give you the study, but also bring in other topics that I teach on how to interpret the literature, critical appraisal, the application of statistical interpretation.
• 20:42
  SPEAKER_00: And that's what we're doing here.
• 20:43
  SPEAKER_00: So an odds ratio of 1.7 does not mean the patient is 70% more likely to recover.
• 20:50
  SPEAKER_00: It means that the odds of favorable outcome were about 70% higher in the Alto Place group than in the placebo group.
• 20:59
  SPEAKER_00: Okay, so odds and probability are not the same thing, especially when the outcome is common.
• 21:06
  SPEAKER_00: And favorable recovery after a stroke is common enough that the odds ratio can sound more dramatic than the absolute bedside effect.
• 21:17
  SPEAKER_00: So, how should we say it clinically?
• 21:19
  SPEAKER_00: And I would teach it this way.
• 21:21
  SPEAKER_00: Again, the one-year data showed a sustained benefit.
• 21:25
  SPEAKER_00: Okay, across functional scales, all to play shifted outcomes in a favorable direction.
• 21:33
  SPEAKER_00: But for a patient or family, the clear number is the absolute difference of about 11 to 13 patients out of the 100 that are treated had minimal or no disability at one year.
• 21:48
  SPEAKER_00: Let me say that again.
• 21:49
  SPEAKER_00: About 11 to 13 patients out of the 100 we treat will have minimal or no disability at One year.
• 22:01
  SPEAKER_00: That is much more useful than saying an odds ratio of 1.7 in isolation, especially to a family.
• 22:09
  SPEAKER_00: Okay.
• 22:09
  SPEAKER_00: Now, how did the later evidence of that study reshape the NINS message from the study?
• 22:17
  SPEAKER_00: Well, the best way to think about this is that the NINS trial opened the door, and later trials and meta-analysis clarified who benefits when they benefit, and how bleeding risk can be framed.
• 22:32
  SPEAKER_00: Okay, so there was a 2014 individual patient meta-analysis involving 6,756 patients from nine altoplase trials referenced a core principle.
• 22:45
  SPEAKER_00: Okay, earlier treatment produces larger benefit, and altoplase improves the odds of good stroke outcomes when delivered within 4.5 hours, despite an increase, okay, listen, despite the increase in early risk of fatal intracranial hemorrhage.
• 23:06
  SPEAKER_00: That same meta-analysis helped to contextualize the bleeding risk.
• 23:12
  SPEAKER_00: Now the early uh hemorrhagic mortality signal is real, guys, but by three to six months, that risk was offset by an increase in disability-free survival, especially when patients were treated early, when that tissue's not breaking down.
• 23:31
  SPEAKER_00: So the modern interpretation is not that the NINS was the final word.
• 23:37
  SPEAKER_00: The modern and more relevant interpretation is that NINS established an important principle, guys.
• 23:42
  SPEAKER_00: Early perfusion can improve functional outcome in selected patients.
• 23:50
  SPEAKER_00: Not all, selected.
• 23:52
  SPEAKER_00: Later data extended and refined that window, emphasize speed, reinforce that hemorrhage is that risk is real, but must be weighted against the disability prevention.
• 24:04
  SPEAKER_00: So there's remember there's a tension.
• 24:06
  SPEAKER_00: Now let's bring this into current practices, right, based on guidelines.
• 24:11
  SPEAKER_00: So they've moved beyond the original three-hour time frame in the ninja trial.
• 24:15
  SPEAKER_00: Okay.
• 24:17
  SPEAKER_00: The guidelines also included the expanded use of tinectoplase or TNK within four and a half hours as a key change from the original NINSH trial.
• 24:30
  SPEAKER_00: Some of the emergency physician guidance guidelines state that either altoplase or tenectoplase may be used for IV thrombolysis in that 4.5 hour treatment window, and that thrombolytic treatment should not be delayed just to obtain multimodal imaging when the patient is otherwise eligible for treatment.
• 24:56
  SPEAKER_00: Now there's another message that's also important.
• 24:58
  SPEAKER_00: It's the do not overuse this treatment message, right?
• 25:02
  SPEAKER_00: So what is that about?
• 25:04
  SPEAKER_00: Well, if you think about non-disabling deficits, guidelines suggest the use of dual antiplatelet therapy is preferred and recommended and recommended over IV thrombolysis.
• 25:16
  SPEAKER_00: That matters because the NINS excluded rapidly improving or minor symptoms, and because the risk-benefit ratio changes when the presenting deficit is not disabling.
• 25:29
  SPEAKER_00: What about TNK or tenectoplase?
• 25:31
  SPEAKER_00: Well, this is where we need to be precise.
• 25:34
  SPEAKER_00: The NINS trial did not study tenectoplase.
• 25:36
  SPEAKER_00: The NINS studied altoplase versus placebo.
• 25:39
  SPEAKER_00: Okay, tenectoplase entered that story later on as a modified tissue plasminogen activator with practical advantages.
• 25:48
  SPEAKER_00: Greater fibrin specificity, longer half-life, and what most people love, it's a single bolus administration.
• 25:57
  SPEAKER_00: I mean that matters in a stroke system because a bolus being given is easier than a bolus plus a one-hour infusion, isn't it?
• 26:06
  SPEAKER_00: Especially during transfers, when you're in a rules setting or a critical access facility and you need to get a patient to a higher level of care to get like something like thrombectomy.
• 26:15
  SPEAKER_00: But tinectoplase, again, did not become relevant because it had its own ninja trial, like placebo compared trial.
• 26:24
  SPEAKER_00: It became relevant because it was compared against altoplase, the therapy whose efficacy was anchored by the ninja trial and later altiplase trials.
• 26:35
  SPEAKER_00: So that's things like the ACT trial, randomized 1600 patients with acute ischemic stroke, eligible for thrombolysis within that 4.5 hours to get TNK at 0.25 milligrams per kilogram maxed out at 25 milligrams, or altiplase at 0.9 milligram per kilogram, which is a dose from the NINS trial.
• 26:56
  SPEAKER_00: Tenectoplase was shown to be non-inferior on that modified ranking score of 0 to 1 at 90 days.
• 27:04
  SPEAKER_00: It was 36.9% for tenectoplase versus 34.8% with altoplase.
• 27:10
  SPEAKER_00: What about bleeding?
• 27:11
  SPEAKER_00: Intraserebral hemorrhage, 3.4% for TNK versus 3.2% in altoplase.
• 27:19
  SPEAKER_00: Another study of the extend TNK is especially relevant for patients with large vessel occlusions who are going to go off to get that thrombectomy.
• 27:29
  SPEAKER_00: Alright, in that trial, TNK improved early reperfusion before angiography, right?
• 27:35
  SPEAKER_00: 22% versus 10% with a symptomatic intracranial hemorrhage of 1% in both groups.
• 27:42
  SPEAKER_00: Okay?
• 27:43
  SPEAKER_00: That is one of the reasons many stroke systems particularly became particularly interested in TNK for large vessel occlusion patients being transferred and moved out of the angiosuite more quickly, right?
• 27:57
  SPEAKER_00: The test II then added trial, then added a broader evidence to the to the mix.
• 28:03
  SPEAKER_00: TNK at 0.25 milligrams per kilogram was non-inferior, but not superior to altoplase for 90-day modified ranking score distribution in a large UK trial.
• 28:17
  SPEAKER_00: So what should a clinician do with all of that, much of which you can't maybe probably remember the details, but use the agent your stroke system is prepared to use safely, rapidly, and early, right?
• 28:32
  SPEAKER_00: In many systems, that may now be tinectoplase, and others, altoplase may still be the established workflow.
• 28:39
  SPEAKER_00: The core decision is not which thrombolytic is fashionable.
• 28:43
  SPEAKER_00: The core decision is whether the patient has a disabling ischemic stroke and is within an evidence-supported treatment window and has had hemorrhage, hemorrhage excluded and has no contraindication that shifts the risk-benefit balance.
• 29:03
  SPEAKER_00: That's the trial in context, guys.
• 29:05
  SPEAKER_00: Okay, and on This Is Why, our show, okay, the goal is to move beyond just what the data show to understand why it matters so that we can apply it more effectively in clinical practice.
• 29:20
  SPEAKER_00: Now, if you'd like a deeper breakdown on this study, there is a free download available at thisiswhy.health if you're interested with some of those key outcomes.
• 29:31
  SPEAKER_00: Just click on the link that's provided in the description at YouTube on our YouTube or podcast, and it will take you to thisiswhy.
• 29:39
  SPEAKER_00: Uh to get that free access to that download if it's interested.
• 29:44
  SPEAKER_00: All right.
• 29:44
  SPEAKER_00: Um, if you haven't already, guys, please give us a like if you enjoyed this or found it to be helpful.
• 29:50
  SPEAKER_00: Subscribe and keep learning the why because that makes the how easier.
• 29:55
  SPEAKER_00: And I'll see you next time.
• 29:56
  SPEAKER_00: Take care.
• 29:57
  SPEAKER_00: Bye.