Transcription
So, it's a tall task to cover advances in STEMI care. So what I'm going to do, uh, as we'll see on the next slide, is I've sort of picked four different areas related to STEMI care: the issue of reperfusion, pharmacological therapy—some of which has already been covered by Dr. Kabani—we'll talk a little bit about cath lab techniques and process improvement. And I've tried to focus really on some of the advances or the newer areas in each one of these areas. So, uh, we still got a long way to go in the next 18 to 20 minutes, so let's start with reperfusion.
I'm just going to begin with a couple of review slides, and I want to focus through these review slides on one of the core principles of STEMI care, and that is that time is very, very important. You can go back to the original studies; these are basic animal science studies that looked at what happens with coronary occlusion over time in terms of resulting in myocardial necrosis. And this curve, which we'll see over and over again reproduced clinically, shows us that the longer the coronary arteries are occluded, the less survivability there is, and that occurs very early. So, even by 40 minutes or one hour, the majority of the damage that will occur has occurred by that length of time. And furthermore, as we get down to about three hours after coronary occlusion, you can see that we reach a rather flat part of the curve where beyond that, not only will they not have necessarily much further damage, but that means our opportunity to intervene and to salvage myocardium is significantly decreased.
Again, by way of review, as we begin to use fibrinolytic therapies in the 80s and beyond, we saw a very similar shaped curve, but instead of being myonecrosis, these are actually lives lost or lives saved. And again, we see that in the very early period, if we can treat people early in the first hour or two, there's a remarkable difference we can make in terms of survivability, but beyond about 3 to 4 hours, our ability to change that goes down significantly. Of course, fibrinolytic therapy was superseded by primary PCI, and again, by way of review, uh, when we compare multiple trials of primary PCI versus fibrinolytic therapy, we just really established primary PCI as the preferred treatment for reperfusion. But the caveats there are assuming it can be done in a timely fashion and in skilled, experienced centers.
So what I want to focus on—two points really in terms of reperfusion, and this spectrum that I have here I think will illustrate that—we know that if people can be treated within the first 90 minutes, primary PCI is the best. There's sort of a gray zone here, and even the guidelines have waffled a little bit in terms of how we treat these patients: What if someone can't be treated within 90 minutes, but maybe the time is between 90 and 120 minutes? And there's been some mixed signals that have been sent: Should they get fibrinolytic therapy, or should they still be transferred for primary PCI? So I'm going to address that number one. And then, secondly, what about those patients who—just there's no way that they can be treated within 120 minutes? I think we all agree they probably should receive fibrinolytic therapy if they are candidates, but then what do we do with them? And I want to address that question as well.
Um, the most recent trial that addresses this sort of gray area—this gray zone, as I said, those who can't be treated within 90 minutes but maybe around 120 minutes—is the STREAM trial. And the STREAM trial was a rather large trial—almost 2,000 patients—and they compared people—these exact people—people that they estimated it would take an hour to transfer these patients. So you do the math, and you realize that their treatment times are going to probably be between 90 and 120 minutes. And in fact, that's exactly uh what they found, as seen in the left chart there. On the right are the results, and you can see there's really almost no separation between these curves. So although people did receive fibrinolytic therapy much earlier on average—almost 80 minutes sooner than they could get primary PCI—there really was no demonstrable benefit, at least in terms of their composite endpoints. In terms of total mortality, there were some slight trends toward improvement in heart failure and shock, but again, it was underpowered and could not statistically demonstrate that.
So the STREAM trial—is it a positive trial or a negative trial? This is a great trial because no matter what your bias is, you'll be happy with the STREAM trial; there's something there for everybody. And what I mean by that is that if you have a bent toward fibrinolytic therapy, you can certainly demonstrate that it was safe and that seemed to be reasonably effective. But on the other hand, and I think looking at it from that gray zone perspective, we really didn't see any additional benefit, although the first medical contact to balloon time was about 120 minutes. And what about the far end of that spectrum—those patients who really are appropriate candidates for fibrinolysis, in other words, their treatment times are going to be beyond two hours? They get lytics. Then what? Uh, many years ago, there was hesitancy to take these patients to the cath lab for concern of bleeding or maybe even thrombosis and occlusion. But I think we have good data at this point through two trials. I'm going to show you the CARET data, but another trial called the TRANSFER-AMI both looked at these situations, and what they found was that even those patients who receive fibrinolysis, it's probably better to, as a routine strategy, go ahead and transport them to centers that can perform angiography, and it's probably better to go ahead and do routine angiography and cleanup PCI as needed.
So in conclusion of this segment, we know that occlusion leads to permanent myocardial damage; we know that fibrinolysis can promote coronary reperfusion and save lives; primary PCI is better; still, for those patients who cannot be treated within 120 minutes, they really should receive fibrinolysis. But among those patients, they probably are best served by urgent, routine transfer for early angiography and PCI as needed.
So in the realm of pharmacological therapy now—Dr. Kabani has already talked—I figured he would talk a little bit about some of the newer antiplatelet agents, particularly prasugrel and ticagrelor. So I've included those just so you have those in your syllabus, but I'm not going to spend too much time; he already went over the TRITON trial and the PLATO trial, essentially showing some additional benefit with these drugs as compared to clopidogrel, particularly in these higher-risk ACS or STEMI patient populations.
Two other points I'd like to make in terms of pharmacological therapy: One I have found interesting, and that's two trials that I'm going to highlight here—the TRILOGY-ACS trial and the ATLANTIC trial. Of course, we've learned from our years with clopidogrel that it was really important to begin therapy early; clopidogrel has to be converted to a bioactive drug; its absorption is slow; and so the thinking was to always begin to load this drug ASAP so we can get it on board. As he's pointed out, the newer drugs—prasugrel, ticagrelor—their uptake is much quicker; their metabolic activation that's needed is very quick. And so I think it's a reasonable question to ask: Do we need to preload these agents? This really wasn't even on my radar, to be honest; I just assumed that we would do that. But it's interesting—these trials have been published in the last year; prasugrel was studied actually in the setting of ACS, whereas ticagrelor was studied in the setting of STEMI. So they're certainly slightly different studies, but surprisingly, they've shown similar results, and that is that we really have had a hard time demonstrating that the loading dose, and particularly the loading dose prior to the cath lab, is highly beneficial. In the TRILOGY-ACS and the TRILOGY PCI trial, there was no demonstrable benefit. In the ATLANTIC trial, which really focused not on clinical endpoints but on angiographic and EKG endpoints, they did not show any advantage with pre-loading of ticagrelor. There was a bit of advantage in terms of reduction in stent thrombosis; that's certainly significant, but a relatively rare event.
And then the last thing in the area of pharmacology I want to talk about is what really has proven to be a very passionate debate over the last year or so, and that is the issue of bivalirudin or heparin. Uh, just to kind of recapitulate how we got here: Back in the late 90s, when unfractionated heparin alone was the standard of therapy, we did a number of large, really well-conducted trials that looked at adding these 2b3a antagonists—abciximab was the one that was predominantly used. Of course, we have eptifibatide and others. And what we found was that unfractionated heparin coupled with the 2b3a antagonist were superior to fractionated heparin alone. Now, granted, we really didn't focus on bleeding a whole lot during that era; there was a little bit higher bleeding, but we felt that we were getting reduced ischemic endpoints. However, uh, in the 2000s, the HORIZONS trial was published, and that studied bivalirudin as monotherapy versus what was the standard of care at that time—heparin plus a 2b3a. And what we found there was equal composite ischemic endpoints, but a significant reduction in bleeding. And really, to our surprise at that time, that translated into a reduced mortality. So although there were equal ischemic endpoints, we saw reduced mortality with bivalirudin, and so that really sort of catapulted bivalirudin to becoming the standard of care for the last five to eight years.
This last year, a trial out of Great Britain—the HEAT-PPCI trial—compared plain old unfractionated heparin by itself, monotherapy, to bivalirudin. And again, sort of to our surprise, we saw reduced ischemic complications. Again, kind of seems like a non sequitur to me as you follow this graph around: Heparin and a 2b3a is superior; bivalirudin is superior; and now plain old heparin is said to be superior. So a few things that don't make sense to me there, uh, but they had equal bleeding. So what do we do about this? I think really the story remains to unfold, and it will over the next one to two years. It doesn't completely make sense. There may be some reasons how we can resolve this tension: Number one, of course, we have more potent P2Y12 receptor antagonists than they did back in the days when we were studying 2b3a; the bleeding issue may be changing as the world is moving more toward radial access and radial interventions; there's a question about inadequate bivalirudin dosing; the ACS, for example, in the HEAT trial were only about 250 on bivalirudin, and that's certainly much lower than we would typically see in our lab with bivalirudin; and it was a single center. So it remains to be seen. For now, I think all we can say is both of these agents are class one indicated for STEMI; both are measurable and verifiable—that makes us interventional cardiologists happy. Current dosing that we're using, which is much lower in terms of heparin than we used in 10 or 15 years ago, seems to be associated with reduced bleeding, and certainly we're using a lot less 2b3a antagonist.
So what do we do at my shop? This is what we've been doing for a number of years; we've not altered that in the last 12 months. We give aspirin; we give a bolus of heparin, uh, without a drip in our ER and outside emergency rooms before they come; and then as soon as they get to the cath lab, we initiate bivalirudin and then give oral antiplatelet agents based upon their bleeding risk, age, and things such as that. And we have a very rare use of 2b3a—probably about 5%.
Okay, moving on to the next area: procedural techniques and adjunctive therapy. A lot of things have been tried; some of these go all the way into the world of the zany to the—seems like a great idea, but really most of these have not panned out. Still, some of these are underway, but what do we have that we can really look at? Well, number one, I think aspiration thrombectomy. This is something that's kind of coming full circle; it seems like there's been a lot of promise; we've had high, high, high expectations, haven't we, about thrombectomy—clears the vessel, allows us to see what's going on underneath thrombus, and that allows us to treat the vessel a little more aggressively. So we've been kind of like this lady who's about to get the ball only to have it snatched away from her. So that's kind of the way there she is—oh.
So why do we say that? Why were our expectations so high? Our expectations were high based really on this trial, which was a large trial but a single-center trial—the TAPIS trial—which looked at aspiration thrombectomy in the setting of ST-elevation MI. And what they showed, kind of surprisingly—almost too good to be true—was a remarkable reduction in mortality. And it was really on the basis of this trial and some other small ones that this became a 2A indication in our STEMI guidelines. But over the last year, or just over a year ago, the TASTE trial was presented—a large trial out of Sweden, about 7,000 patients, also looking at thrombectomy—aspiration thrombectomy in the setting of STEMI—and there was just absolutely no separation of these curves, as you can see on the top right. So there's no mortality benefit there. So the guidelines have not been updated since this time; I think they're likely to be downgraded this technique to 2B, but it's unlikely that it's going to go away, um, because it it does have some benefit. I think anybody who does coronary interventions can see that there are certain situations where we would still like to use that.
What about the issue of stent selection? I think this is mostly going away, but six, eight years ago, there was concern about stent thrombosis associated with drug-eluting stents. And so that really raised the question—particularly in a subset that has high thrombus burden to begin with—are drug-eluting stents a good idea? A couple—many trials have been done; I'm just going to highlight a couple of the larger ones—EXAMINE and COMPARE. We expected to see a significant reduction in target lesion revascularization—their drug-eluting stents—that's what they do. But I think the really important aspect of these trials was that they saw a reduction in their composite endpoints, which was death and infarction. But they also saw—not only did they avoid an increase in stent thrombosis, but actually saw a reduction in stent thrombosis. But these are again with our current generation drug-eluting stents, which seem to be less prone to late thrombosis than some of our early generation drug-eluting stents.
And then finally, the last issue technically, and this is kind of a provocative section I wanted to throw in, and that is the issue of multivessel PCI. The background is that PCI of a non-culprit lesion in the setting of STEMI, of course, it's been class three for many, many years. But many people over the last two to three years have said, "You know, PCI has changed; there's much greater consistency; there's much greater predictability; our pharmacotherapies are much better in terms of anticoagulation, antiplatelets, and all of those issues." And it's really into that environment that these two trials have been presented over the last 12 months: The PRAMI trial, which is now published, and the CULPRIT trial, which has been presented but has not yet been published in the peer-reviewed literature. And these were trials that randomized patients to either culprit-only treatment during STEMI or treatment of all significant stenosis in the same setting as STEMI. And not surprisingly, that lowered revascularization and angina. But what is surprising is that it lowered, actually, recurrent myocardial infarctions. And you can see there on the slide—this is from the PRAMI trial—there was a significant reduction in the primary endpoint with what they deemed preventative PCI or multivessel PCI. Critiques exist; certainly these are not huge trials; they're relatively small, um, and they examine same-setting multivessel PCI versus culprit only. They don't really address a situation that many of y'all may be thinking: Maybe we bring them back in a few days, a few weeks. That will be addressed in the COMPLETE trial, uh, which will be a very large trial—4,000 patients—that will really definitively answer this question. But we don't expect the results for a few years.
And then the last issue I want to deal with is this issue of process improvement. We all know that we can do great science, and we can come up with great ideas, but if we can't translate those into reality, then we're not going to achieve the goals that we want to achieve. And that's going to really require developing what we call STEMI systems of care. By definition, very simply: An integrated group of entities within a region, coordinated services. The focus has been largely on the primary PCI center and getting our house in order, but we realize now that that's not good enough; that we're going to need to work together collaboratively with prehospital personnel, with non-PCI hospitals, and we really need to be thinking ourselves in an integrated fashion—a challenge, certainly, for the US health care system.
Why is that? Well, this is four-quarter data from the ACTION registry. In the green are the times of patients that takes to treat who present directly to a PCI hospital, and those are very good; those are under an hour; there's really exceptional, I would say, but for those who do not present directly to a PCI hospital, their times are still 100 to 120 minutes. So how are we going to address that? Well, I want to end up on addressing sort of two issues: The primary PCI center again, I think has done an excellent job of improving STEMI care, but the areas that we need to focus on are number one, the non-PCI hospitals. And the non-PCI hospitals is really where about 40% of the patients present, and when they have to spend a few minutes in those hospitals before being transferred, we're losing valuable time. The RACE group has studied this, and they found that essentially if you spend more than 30 minutes in a referring emergency room, then your treatment times are going to be compromised, and that's going to translate into higher mortality. And so we really have to work with our PCI—I'm sorry, our non-PCI centers—to help them improve their processes, uh, so that they can get patients in and out within 30 minutes. And I'm not going to spend time, but in your syllabus are various ideas of best practices for how they can do that.
And then, of course, the last thing would be working with EMS directly. We know those EMS runs that are perhaps halfway between a PCI and a non-PCI center—that's a no-brainer; they need to be rerouting to a non-PCI center. But what about those EMS groups that would actually have to bypass a non-PCI center to get to a PCI center? Is that possible? Is that a good idea? Again, this represents about 40 to 60% of our population, but as BRAGI-NTHU has shown, three-quarters of those patients could be transferred in less than 30 minutes. So this is really a feasible strategy. In this large study—581 patients—that looked at this exact thing—these are all patients who were diagnosed in the prehospital setting with prehospital ECG—80% of them were then transferred directly to a PCI center. And what did they find? They found number one, it was safe; there were no deaths—did get exciting; there were some VF, but no deaths in route—and what they found was that treatment times were greatly enhanced, and that greatly enhanced treatment time resulted in significantly reduced mortality. So again, best practices—I included those in your syllabus—a lot of things that we can do, and we need to be partnering with our EMS agencies to improve care for everybody.
So in conclusion, STEMI systems of care are now a societal expectation. The concept of treatment times—we can no longer just think about door-to-balloon times, but we really have to think about the entire health care system and how much time is taking for patients to be treated. PCI centers will take the lead, but again, we really need to be working with our EMS partners as well as our non-primary PCI hospitals as well to bring them on with the team. So with that, I apologize for running over just a minute. Uh, thank you for your attention, and I invite you guys to follow us at STEMI Texas, the website, and then our meeting will be held each fall.