Volume 90%
Press shift question mark to access a list of keyboard shortcuts
Keyboard Shortcuts
Play/PauseSPACE
Increase Volume
Decrease Volume
Seek Forward
Seek Backward
Captions On/Offc
Fullscreen/Exit Fullscreenf
Mute/Unmutem
Seek %0-9
00:00
00:00
00:00
 

Chapters

Transcript

 

MANDEEP SINGH: Good morning, everyone, and welcome to the webcast on Acute Coronary Syndrome. My name is Mandeep Singh, and I'm the Professor and Director of Acute Coronary Syndrome for Mayo Foundation. And on behalf of the Cardiovascular Department at Mayo Clinic, it is my distinct honor and privilege to welcome Professor Bernard Gersh, who is my teacher and mentor. And we are so lucky to have him.

Just to give the audience a brief introduction about him, he's a professor at our Department of Cardiovascular Diseases. He received his doctorate of philosophy from Oxford University, where he was the Rhodes scholar as well. He has authored, co-authored more than 1,200 publications. He sits on the editorial board of more than 27 journals. He has been nominated Teacher of the Year multiple times, has visited almost every country in the world as a visiting professor.

He has received Distinguished Achievement awards, both from American College, American Heart Association, from University of London. He has been the most cited author from 2002 to 2012, and most recently in 2020, and has received a Distinguished Scientist award. And I don't think he needs more introduction. So we are so lucky to have him, and I welcome him. And he's going to speak on reperfusion therapy in STEMI. A case he's going to make for pharmacoinvasive approach, even in the USA. Professor Gersh, welcome.

BERNARD GERSH: Thank you very much, Mandeep. It's a great pleasure to be here, and to be part of this webinar today. I'm going to talk about reperfusion therapy for STEMI, but really make the case for the pharmacoinvasive approach even in the United States. There's no question that in many parts of the world the pharmacoinvasive approach is the only realistic option, but I really wanted to point out that applies to the US as well.

So the learning objectives are to emphasize the relationship between time and muscle in terms of reperfusion therapy, to identify the rationale and the pitfalls of a systems approach to reperfusion therapy in the community, and to identify situations in which a pharmacoinvasive approach may be superior to primary PCI. I think we all agree that primary PCI is the best option, but it may not be-- that may not apply to every part of the country or other countries. And in a community setting, I want to talk about where the role is of primary PCI versus the pharmacoinvasive approach.

Now, when we talk about time as muscle, we go back to the classic experiments of Reimer and Jennings, 1979. They really heralded the reperfusion era. And what they showed in dogs with coronary occlusion is progression of necrosis with time. 40 minutes after occlusion, 64% of the ischemic myocardium is viable. The gray here reflects necrotic transmittal infarction, and the red nonischemic.

After three hours of occlusion you can see that the wavefront of necrosis has expanded, and now only 11% of the ischemic myocardium is viable. And after 96 hours, only 9% of the ischemic myocardium is viable. So this really provided the rationale and the impetus for the reperfusion era, with the understanding that if you could open an artery and restore blood flow within a certain time window, you could salvage myocardium.

Well, it's important to realize that there are marked species differences in this relationship. And I ask you the question here, why does the Guinea pig when the rat race of life compared to the domestic pig? Well, the Guinea pig has a very, very extensive collateral circulation, and the domestic pig has a very poor collateral circulation. And humans, probably in terms of collaterals, as a species, we tend to be closer to the domestic pig than to the Guinea pig, which means that the window of opportunity is much narrower than in many other experimental animal species.

The impact of time delay after primary PCI was recently shown in this very comprehensive and nice study from Redfors and Dr. Greg Stone, published in Circulation Intervention, 2021. 3,000 patients from 10 randomized trials. And infarct size was looked at by SPECT in 3 studies, and CMR in seven studies. And infarct size was measured within a month of the timing of the initial infarct.

They stratified patients according to the symptom-to-balloon time. Short, less than two hours. Intermediate, two to four hours. And long, greater than 4 hours. And by door-to-balloon time, which door being presentation to the hospital or the cath lab. Short, less than 45 minutes. Intermediate, 45 to 90 minutes. And long, greater than 90 minutes. And if you look at infarct size stratified by short balloon-- symptom-to-balloon time, and door-to-balloon time, what you can see, if you just focus here on long, you see that people with a long presentation time had a much larger infarct size.

And really, what I want to emphasize with this slide, is probably the period where we can modify time delays. The greatest is from the presentation, from the onset of symptoms to seeking care in the hospital. That's the period that accounts for the longest period of delay, and is probably the most amenable to measures to shorten that period.

If you look at microvascular obstruction again, those with a long symptom-to-balloon time had a much greater degree of microvascular obstruction. Symptom-to-balloon time carries greater weight than door-to-balloon time. And then ejection fraction. Here, those with a long symptom-to-balloon time had a marked reduction in ejection fraction, or significant reduction. And also those with a long door-to-balloon time had a lower ejection fraction.

Now, the relationship, in turn, between infarct size and mortality is shown here. Another study from Dr. Stone's group, 10 trials, 2,400 patients. MRI infarct size assessment in 72% and SPECT in 28%. And if you look at the quartiles of infarct size, the yellow being 1% to less than 8%, and blue being greater than 29.8%, you can see a very striking effect on mortality within the first year, ranging from almost 9% down to 1.2%.

So really, this, again, is the rationale for reperfusion therapy, that if you can salvage myocardium and reduce infarct size, you will have a major impact on mortality. Now, this is a study that's in press. And there's a rather sad story attached to it, in that it's a prospective registry of 55 interventional centers mainly in Europe and the UK, of patients with COVID-19 positive, or high index of clinical suspicion, who presented with an acute coronary syndrome.

Now, the individual who put this registry together was Tony Gershlick from the United Kingdom, and sadly, he died of COVID. He was one of the real pioneers of interventional cardiology in the United Kingdom. And I was fortunate to be able to work with him on this registry. And again, somewhat sadly, the last time we spoke was in regard to this paper that we were submitting to JACC. And this paper really emphasizes time is muscle.

I want you to look at the STEMI subgroup, 145 patients. The pre-COVID data came from two large UK databases that were established in the year before COVID-19. If you look at symptom to admission time, it was previously about 179 minutes, about three hours. During COVID, it went out to over five hours. People were scared to come to hospital. They were nervous about coming to hospital.

Door-to-balloon time very short in the year before COVID, 37 minutes, now doubles. And what impact did that have on mortality and the development of cardiogenic shock? These results are quite shocking really. In-hospital mortality totally was about 5% in the year before. Went up to 23% with STEMI. Cardiogenic shock more than doubled from 8.7% to 20%. So this is really time is muscle on steroids, so to speak. Really a striking and a tragic example of what delays can do, and how they can affect outcomes.

Now optimal care, we know what to do. We know primary PCI is the best form of therapy. I don't think there's any argument about that. But there are a number of constraints that may impact the efficacy of primary PCI-- geography, distance, weather, mode of presentation, whether it's 9-1-1 or hospital, coordination of services, both at an institutional level and a regional level, and the allocation and availability of resources. So we know what to do. The question is, how well can we deliver care?

This is Olmsted County. Mayo Clinic is here in Southeast Minnesota. We don't have traffic issues. We've got two, three helicopters in the field, one based at St. Mary's Hospital in Rochester. But what we do have is weather. And this is a winter storm, and this is a storm in the summer. And when you start seeing red and orange, this means a tornado watch. And if you-- I don't know exactly what it was last year, but most years the helicopter and air transport is grounded for about 40 to 50 days of the year, for at least part of the day.

So you need to have a system that can account for that. And when you have these delays, it's when you need alternatives to primary PCI. Now, this is from a paper that I published in JAMA in 2005. And this is a hypothetical construct of the relationship between mortality reduction and extent of salvage. And the other authors were my colleague David Holmes, Dr. Greg Stone, and Dr. Harvey Whiting from New Zealand. He's played a big role in the reperfusion era.

And what this slide shows is, on this axis is the duration of ischemia prior to reperfusion. On this axis, the black line, the thick black line, is the mortality reduction in percent. Everything under this black line reflects the extent of salvage as a percentage of the area at risk. And this is the impact of treatment delay. And what one can see highlighted here is, early on in the first one to three hours, time to treatment is critical. Time is muscle.

Thereafter, when you get out onto the flat part of the curve, it really doesn't matter whether you open the artery here, or here, or here, or here. What is important is that you open the artery, the infarct related artery. And in this part of the curve, PCI will always be more effective than thrombolytics. But here is the window of opportunity.

And the question, and the entire rationale of the pharmacoinvasive therapy is this, if you have a patient that presents to a community hospital without a catheter after 50 minutes of symptoms, and it's going to take you an hour to transport that patient to an institution with a cathetoer, and you're on this part of the curve, how much delay is acceptable to get the better therapy, which is primary PCI as opposed to getting lytics and transferring the patient for primary PCI?

And that's the key question. And then there are all these modifying factors. I mean, this was a hypothetical construct, but in fact, the subsequent data produced by Stone and others really showed that by and large, we got it right. But modifying factors-- collaterals, ischemic preconditioning, myocardial oxygen demands, stuttering infarction-- but what I believe will be an absolute key in the next five to 10 years is understanding the impact of microvascular dysfunction.

So reperfusion strategies for STEMI. What I've shown here is a diagram from the ESC guidelines on STEMI, published 2017. The USA ACCHA guidelines are very similar. It's just that the most recent are the ESC guidelines. And they look at total ischemic time shown on this axis, patient delay, EMS delay, and system delay. And the first two scenarios are patients who are transported by emergency medical systems services, and patients whose first medical contact is at a non-PCI center.

So this applies really to community approaches in patients presenting to a center that may not have a cath lab, or alternatively, who are transported by ambulance. And really they divide the system delay, the time delays, into two. Time to PCI, less than 120 minutes. Time to PCI, greater than 120 minutes. Now, if in fact, you can transport a patient within 120 minutes, that's to first to primary PCI, if you can do it within 120 minutes then primary PCI is the preferred strategy.

But they categorically state, if the whole process is going to take longer than two hours, then you need a fibrinolytic strategy followed by transfer. On the other hand, if you have a patient who comes to a PCI center, then the only strategy that really you can justify is primary PCI, but it needs to be done within 19 minutes. One of the areas of greatest delay is in patient presentation and in transport time.

But the ESC guidelines I think really lay down very clearly that if delays are greater than 120 minutes, you should be using fibrinolytics, all things being equal. And by that I mean it depends on the risk of bleeding. Now, this is a study from the United States, and illustrates driving times and distances to US hospitals with primary PCI facilities. And what you can see, that in most of the country, the prehospital time period to PCI hospital is less than 60 minutes, shown in blue.

And if you look at our metropolitan centers on the West Coast and the East Coast, Florida, up here and near Seattle, Chicago, the large metropolitan centers, there's no shortage of cath labs looking for business, and prehospital time period is less than 60 minutes. But look at other parts of the country, the Rocky Mountain areas and parts of the Midwest, where the prehospital time period to PCI hospital is greater than 60 minutes.

79% of patients live within-- 79% of patients live within 60 minutes of a PCI hospital. But let me turn it around, 21% don't. And driving times from a non-PCI to a PCI hospital are less than 30 minutes in 74% of patients, but not for 26%. So we need a system, again, I emphasize, we all agree that primary PCI if performed expeditiously is the best form of treatment, but we need to account for this 25%, 30% of patients where they cannot get to a PCI hospital expeditiously, in an appropriate time.

So you need reperfusion networks. And this, in both guidelines, is a Class I indication-- set up a network. The network needs to have clearly understood and articulated goals based on evidence. And the objective is not to compete for patients. The objective is to enhance the speed and delivery of reperfusion therapy to all eligible patients in the community. It has to adjust to local conditions. Everybody needs to buy in.

Everybody involved needs to understand their role, and buy into it. It needs to be simple to follow up, and it needs to function seven days a week, 24 hours a day. It needs to be continuously audited to monitor your performance and adapt to new knowledge. And this is what we've done at Mayo. We have a network that covers 150 miles, a network of hospitals within a 150 mile circumference. And we stratified our patients according to the duration of symptoms.

If their symptoms are relatively short, and we can achieve primary PCI within 120 minutes, that's one pathway. If their symptoms are greater than two hours, and we will not achieve primary PCI within that time, they have a different pathway. In this group, that have duration of symptoms relatively short and need to be transferred-- I want to point out here again this is in community hospitals. If they come to St Mary's Hospital in Rochester, they all get primary PCI.

But this is how we deal with patients who need to be transferred. Relatively short duration of symptoms, fibrinolytics, and then they transferred, preferably by helicopter, depends on the weather, and they will have a routine angiogram after about three hours after the onset of symptoms. That's the pharmacoinvasive strategy. If on admission to the PCI-capable hospital, they have persistent symptoms, about 30% of them will go to rescue PCI.

If they have a long duration of symptoms, and they're on the flat part of the curve-- oh, I beg your pardon, there are a number of clinical trials that at one stage advocated watchful waiting, but we don't do that [INAUDIBLE]. They all go to a routine angiogram. Now, if they're on the flat part of the curve, greater than 120 minutes, now time is not of the essence. And what we do is transport them the best way we can, and they will undergo routine angiography and PCI after admission.

Do we facilitate with fibrinolytics in this case? No. This was a concept that was proposed five to 10 years ago, that all patients would have fibrinolytics en route, and we don't do that now. The risk outweighs the benefit. We save the pharmacoinvasive approach for those patients with a relatively short duration of symptoms. And in those on the flat part of the curve, we believe that simply getting them to a cath lab and not exposing them to the risk of bleeding with fibrinolytics is preferable.

So what are the results? This was from my colleague Dr. Siontis, published a few years ago. 1,700 patients at that time over an eight year period. If you look at all cause 30-day mortality and all cause overall mortality, actually the primary PCI group have a higher mortality than the pharmacoinvasive. But remember, this is not a trial. These groups are different. So when we did a multivariate analysis, we actually showed that the hazard ratio is not significantly different between the two groups.

But what is reassuring about this is that the pharmacoinvasive strategy, which is employed in a minority [INAUDIBLE] who have short duration of symptoms but need to be transferred for primary PCI, in that group, that minority of patients, what our data show is that the pharmacoinvasive strategy is not inferior. And I think that that's encouraging. This again, is from a Dr. Gershlick. And this is from the stream trial of the pharmacoinvasive strategy. And these are data on 30-day death, heart failure, and shock.

And what you see-- I beg your pardon-- what you see is in patients who present early, if the PCI related delay, in other words, if the delay involved in taking the patient to a PCI-capable hospital, if the delay is less than 30, 40, 50 minutes, primary PCI does better. But when you look at the patients where the delay in transporting them may be 120 minutes or so, then the pharmacoinvasive strategy looked better.

Now, this is a post hoc analysis, but I think supports the theory. So to summarize, if you have a relatively short duration of symptoms, and time is muscle, and you have a short delay in transfer, they should go to primary PCI. But if in fact, the delay is considerable in transferring them, they should have the pharmacoinvasive strategy, depending upon the risk of bleeding. And I think that's borne out by this subset analysis.

Now, a lot of work in this area has been carried out by doctors Armstrong and Welsh in Alberta, Canada, in Edmonton, actually. And this is their registry data. 3,300 patients, pharmacoinvasive strategy, 55%. And I might point out that Northern Alberta is a bit like parts of the Midwest, long distances, and large distances, and uncertain weather conditions. If you look at their pharmacoinvasive strategy in yellow in primary PCI, ST segment resolution of greater than 50%-- actually greater in the pharmacoinvasive one.

That suggests salvage. The rapidity of ST segment resolution is a surrogate for salvage. If you look at death, heart failure, shock, and recurrent MI, the pharmacoinvasive strategy actually did better. And if you look at major bleeding, there was no difference. In terms of intracranial hemorrhage, 0.6% versus 0.6%. Why do networks fail? And the possible explanations, there are several, because there are honest reports of networks that have failed. I've shown you networks that have worked.

First of all, learning from others. Read history or relive it. If you're going to set up a network, talk to others. Failure to adapt to local regional circumstances, lack of universal buy-in, lack of resources, and the commitment of dedicated individuals. A network involves flight nurses, dispatch people, communications people, physicians, referral physicians, a lot of people are involved. And they all have to, first of all, buy into it and be committed.

And this is an example of what you don't want, a lack of commitment and dedicated individuals. A college basketball coach talking to a player. I told him, son, what is it with you? Is it ignorance or is it apathy? And he said, coach, I don't know and I don't care. Well, I can tell you, having seen the people involved in Mayo and other networks, these are very committed, dedicated individuals, who do a great job in making the network work.

One size does not fit all. You have to work out what's best for you. Here is a cautionary tale and a reality check. It's our US National CV data registry of 22,000 patients. A very good paper from Dr. Vora in JAMA Internal Medicine. And this is fibrinolysis use among patients requiring inter-hospital transfer. It's a complex slide and I want to take you through it.

In this large database, this is the proportion of patients who were able to have a drive time of less than 30 minutes from a community hospital to a hospital that could perform PCI. And amongst these patients, you had a drive time of less than 30 minutes. First door-to-balloon time less than 120 minutes, 67%. And only 6% had fibrinolysis. That's probably appropriate.

One would hope that it would be higher, because the guidelines state that if you longer than 120 minutes you really need to have fibrinolytics. But what about the patients where the drive time was 31 to 45 minutes, or 46 to 60 minutes? Now, only about 40% to 50% had a door-to-balloon time less than 120 minutes, and only 20% to 30% had fibrinolysis. And if you look at those with the drive time of greater than one hour, only 30% had a door-to-balloon time less than 120 minutes, and only 50% had fibrinolysis.

And I would argue that nearly all of them should have had fibrinolysis, providing there was no unacceptable risk for bleeding. And in fact, the median estimated inter-hospital drive time in this US National registry was about one hour. So you really have to ask yourself, well, are we adhering to the guidelines? And this is why I go back to the title of this presentation, even in the USA we have no shortage of cath labs.

But it's a large country, and large distances, uncertain weather, and the question is, how well do we do in terms of treating people within the guidelines? And I do think the guidelines, again, emphasize that if you're going to be greater than 120 minutes, you should consider the pharmacoinvasive strategy. Now, this is from the race registry in North Carolina, a paper by Dr. Jamie Jollis. And what they've done, these are the five regions of North Carolina, and illustrate, again, one size does not fit all.

In some parts of the state, they are transferred for PCI. Others get fibrinolysis, the pharmacoinvasive strategy, and others have a mixed approach. One size does not fit all. And even in a diverse state like North Carolina, what works in some parts of North Carolina, won't works in others where the distances and conditions are different. What about Europe? This shows you primary PCI per year for a million inhabitants.

In many parts of Europe, where distances are very small, it is easy to do primary PCI. Easy, simple. Czech Republic, [INAUDIBLE], 95% of patients get primary PCI. In other parts of Europe, it's more difficult, and distances a much larger and longer. And if you just look at countries in the European Union, you see great striking example of one size does not fit all. This is the Czech Republic. Nearly all get primary PCI. And this is Switzerland. The majority get primary PCI.

The UK has changed now. The majority do get primary PCI, but not at the time that this was published in 2009. Some of the best work in this area has being done by Dr. Thomas Alexander in Southern India, in the state of Tamil Nadu. And he really has illustrated how systems of care can change the entire management of myocardial infarction in a region of India. And he set up the hub and spoke system using the pharmacoinvasive strategy.

And in fact, made a huge impact that came to the attention of the Indian government at a federal and state level. But as he says in this editorial, requires greater treatment and support in the coming years. You really need individuals, but you need resources. And again, what works in Tamil Nadu may not necessarily be optimum for a country like the Netherlands. Australia, wonderful place, but it does have its limitations. Once you get beyond the coastline, you're dealing with huge distances, and a very different system is in place using the Flying Doctor Service and aircraft.

So key messages, delivery of care to patients presenting in non-PCI capable centers. Again, I want to emphasize that if the patient arrives at the door of a PCI-capable hospital, no one will argue that the best treatment is primary PCI. Timely transfer for primary PCI is our biggest challenge. Gosh, 50% of patients or more, greater than 50%, have a first door-to-device time of greater than 120 minutes. And these people, if we follow the guidelines, should in the majority be treated with a pharmacoinvasive strategy unless the risk of bleeding is unacceptable. And that's a clinical judgment.

Emergency medical services taking patients to a non-PCI center, followed by ground transfer for primary PCI, is what I would call a system failure. In large cities or areas where you have non-PCI capable hospitals within three to five miles of a PCI-capable hospital, you should transfer the patient for primary PCI. Not to another hospital, and then require another transfer. The major component of delay and transfer is what is called DIDO-- door in, door out. That is, the time it takes from presentation to a non-PCI capable hospital, to be transferred to the PCI-capable hospital.

And the major delay in DIDO is in obtaining transportation. Just think of that, obtaining transportation. Do you have to call an ambulance from elsewhere? Do you have to call a helicopter from elsewhere or is the helicopter in close proximity? In transportation times generally are greater than 45 minutes, the general strategy should be lytics followed by immediate transfer. Now, if the patient is a 90-year-old female, 50 kilograms body mass index, bodyweight, I would not give lytics because the risk of bleeding is too high. You need to use clinical judgment.

Even then, a plan for the most timely transport of lytic ineligible patients, not patents, is needed. And again, I want to emphasize this is the area where we can have the greatest impact on outcomes, and that is shortening transport and times from non-PCI capable to PCI-capable centers, and using the pharmacoinvasive strategy. There are other unresolved issues. We still argue about the optimal fibrinolytic dose with age, ethnicity, the role of ticagrelor versus clopidogrel.

The optimal window for an invasive strategy. What do we do with patients who have multivessel disease? When do we treat the nonculprit vessels? At the same time or at a later stage? The whole issue of microvascular dysfunction is fascinating and we need more-- to learn a great deal more about it. Improving outcomes and cardiogenic shock I think is the key. And I'm involved in a trial right now, a pilot study in Germany, where we're looking at ways of improving myocardial salvage and cardiogenic shock with remote ischemic preconditioning and prehospital intervention strategies.

So primary PCI for all is a worthy goal, but for the majority of the world, the pharmacoinvasive strategy is the only feasible and logistical option. And I would say for much of the United States. Not the majority, but for a substantial proportion in the United States. It also is a feasible and logistical option. The realistic goals are to reperfuse to as many and as quickly as possible. And in 2021, it's not just the nature of the therapy, but the efficacy of its delivery. And the key is to give it to as many eligible patients, and as quickly as possible.

I want to close with one other slide. This is from an article by Dr. Tom Luscher in the European Heart Journal. And really just shows 1950, 45% mortality with STEMI. And that was the introduction of the coronary care unit and DC defibrillators. And now, in the modern era of reperfusion therapy, we're down to an overall mortality of 10%, and that includes cardiogenic shock. And then people without cardiogenic shock, more like 4%. So what a wonderful 60 years, if you think of it, 70 years.

And the advances that we make from here on will be smaller. The impact will be smaller in magnitude, but this will come down further. I'm confident about that. Well, thank you for the opportunity of being part of this webinar, and I look forward to questions.

MANDEEP SINGH: Thank you, Bernie. This was wonderful. I just have a couple of questions on my own. So we recently changed our protocol for fast track, and laxed the time from two hours to six hours for inclusion, as most patients were not able to present within the two-hour window. My question to you, as we are looking at our own mail health system sites, that the bottleneck, as you rightly pointed out, is the lack of transport, timely transport, of these patients.

And well, most of these sites are not able to maintain the door in, door out time. And sequential delays in transport, it just leads on to delays in us not maintaining our door-to-balloon time for Mayo Health system sites to within two hours. So my question is, one, what is the equipoise between doing a primary PCI, given the delays that we see, as you said, you read history or relive it? Or we just continue?

Because transport things will not change what we have unless we dramatically ask the ambulances to start driving these patients to a PCI-capable hospital, or we change the strategy to pharmacoinvasive approach, given the higher [INAUDIBLE] two, three, flow rates to about 80% to 90%, reduce heart failure, shock. The adoption rate of eligible patients, even in our own spoke sites, has been very low.

Because I think the buy-in from the stakeholders is, either I can transport the patient with maybe 10, 15, 20 minutes extra delay, or I take the task of giving lytic therapy, which is more onerous to the Mayo Health system site, for example.

BERNARD GERSH: Well, I think that-- I mean, I think you really illustrate that one size does not fit all. You are absolutely right. The universal buy-in is critical, but it's not easy to get the buy in for the pharmacoinvasive strategy. And the reason being, it's not just the work involved, it's have to give the lytic and then you are actually responsible during that period of time if the patient bleeds.

Now, in parts of the world where they still use streptokinase, giving streptokinase is not easy. They get hypertension. And it is just easier to put them in an ambulance and transfer them. And then the patient is someone else's problem, because they're on their route to the PCI-capable hospital. I still think that, in many ways, I think the situation in Alberta, from what I've seen, and I've been up there, is much more analogous to where we are in the Midwest at Mayo. And they have been successful in having people adopt the pharmacoinvasive strategy.

And their results, I think, bear that out. So it may be that they can do that in Northern Alberta, but we may not be able to do that in Minnesota. We have to have universal buy-in. And if people are not going to buy into that, we have to do the best we can. I mean, I think the whole issue of door in, door out is the one area where one can improve the outcomes of reperfusion therapy. And in Europe, they've been able to do this in most countries pretty well, but we're dealing with very different distances.

MANDEEP SINGH: Yeah, yeah. No, thank you for that.

BERNARD GERSH: Distances and weather. I still think that-- what I hate to see is someone young enter infarcted [INAUDIBLE] two to three, not that well, and they pitch up at one of our non-PCI capable hospitals at a time when the helicopters are grounded. And that's up to 50 days of the year when they may be grounded for part of the time. Not for the whole day, but part of the day. And that patient-- and we've all seen this, I've seen that patient then arrive three to four hours later without getting a fibrinolytic.

And I remember very well seeing a patient who arrived at a hospital outside our network that was not PCI capable in exactly that situation, was placed on a helicopter, and then that helicopter was diverted because of weather and ended up somewhere else. And this individual, aged 42, 43, I think, ultimately got primary PCI four to five hours after presentation, with a big anterior infarct, and in fact had all the complications of a big anterior infarct. Surely that patient should have had the pharmacoinvasive strategy.

MANDEEP SINGH: Yeah, yeah. We have a question from Dr. Richard [INAUDIBLE]. And he's asking-- one, he said, great presentation. But then he also asked you, can you tell the participants what is the difference between pharmacoinvasive and facilitated PCI? And then, and the second part of the question is, he says some people give half dose. Can you explain when do you give half dose lytics in pharmacoinvasive approach.

BERNARD GERSH: Right. Two very good questions, and thank you for your comment. The pharmacoinvasive, it's actually almost semantic. The pharmacoinvasive strategy was routine lytics and then transfer. I beg your pardon, facilitated PCI was routine lyrics in everybody prior to transfer, and then immediate PCI. So you would have a patient who would present at an outside hospital. They would get full dose lyrics, and they would be transferred and go straight to the cath lab one hour later.

And that was abandoned. High rates of bleeding. And this was a strategy that was developed by the late Dr. Alan Ross. And that was a ban eventually. I'm not sure if we did it now, if we would have the same rate of bleeding. The pharmacoinvasive is fibrinolytics followed by transfer, and then delayed PCI. In other words, they wouldn't have immediate PCI. The guidelines say wait three hours and do an angiogram between three and 24 hours.

So the difference is pretty nuanced. One is an immediate angiogram on arrival. The other is waiting up to three hours. With one exception. About 35% of our patients required rescue PCI. And that is, they had the lyrics on arrival at St. Mary's Hospital. They still had ST elevation, they still had pain or some symptoms, and they went straight to the cath lab for rescue PCI. That figure of 35% has come up in other trials as well. So about a third of the time, the lyrics; lytics may be initially effective, and then become ineffective or they rethrombose, and that's 37%.

And in fact, the culprit trial was-- at least the rescue trial was another trial of Dr. Gershlick's showing that in people with persistent symptoms, take them immediately to the cath lab. So let me just quickly summarize. Facilitated-- lytics, transfer, immediate angiography, that's facilitated. Pharmacoinvasive-- lytics, transfer, rescue in a third, otherwise a delayed angiogram after a minimum period of three hours.

So if a patient comes in at 5:00 in the morning, they're completely stable, you can wait till 8:00 o'clock, 9:00 o'clock, 10:00 o'clock, or whatever, and do it [INAUDIBLE]. Now, the second part of it, in terms of the half dose, when they did the STREAM trial, which is the trial run by Dr. Armstrong in Alberta, Canada, but carried out around the world, there was an unacceptable rate of bleeding with TNK in patients over the age of 75.

So at that time, during the course of the trial, it was half dose. I think it was half dose TNK, and maybe enoxaparin over the age of 75.

[INTERPOSING VOICES]

Was it half dose TNK and half dose enoxaparin?

MANDEEP SINGH: Yeah.

BERNARD GERSH: Or full dose TNK? [INAUDIBLE]

MANDEEP SINGH: Yeah, yeah. You're right.

BERNARD GERSH: Half dose of both.

MANDEEP SINGH: Yeah. And then they also did not give the bolus for the antiplatelet therapy too. I mean, that's the other question I think that may also come up. But go ahead.

BERNARD GERSH: Carry on.

MANDEEP SINGH: So I was just saying that elderly patients, that is one subset where you will give half dose lytics in pharmacoinvasive approach. The other question I have, from Dr. Murphy, he also compliments you for your great talk. His question is, now, you've shown this graph of time to salvage. And so, if a patient presents more than 120 minutes to a non-PCI hospital and has ongoing chest pain, what would you do? Would you give lytics and then transfer? Or would you send the patient again to a PCI-capable hospital for a primary PCI?

BERNARD GERSH: I think-- I just want to be sure I understand the timing here. So a patient comes, they have ongoing pain. The duration of symptoms is relatively short?

MANDEEP SINGH: Yeah, about 120 minutes.

BERNARD GERSH: Well, you're right on the threshold. I mean, basically to simplify it I would say this, if I could get that patient to a cath lab within 120 minutes of presentation, and they've got a relatively short duration of symptoms, then I would just send them straight to the cath lab. But if that patient's got ongoing pain, they'll really two hours out, and it's going to be another two hours of transport, then I would give them the pharmacoinvasive.

MANDEEP SINGH: Now, do you stratify, or do any literature that stratifies patients based on the risk? For example, there is a very high threshold for giving, for example, thrombolytics in elderly, or patients who have different kind of infarcts. For example, a lower risk infarct, like an inferior versus a large infarct, that you pointed out in your discussion, like a large anterior infarct. Do you have a sense of-- do you think it should be universal, or do you think it should be stratified based on the risk?

BERNARD GERSH: Yeah, it's a good question. I mean, there is a literature on that. And I've heard the argument, is it anterior? Is it inferior? Is it a low risk inferior without heart block, and so on? But I think that just complicates it. I mean, I think my own clinical assessment would be the greater the risk of bleeding, the more that would dissuade me from giving a lytic. So sometimes when I show a patient, I show an 87-year-old woman with a history of hypertension, low body mass index, who presented to a hospital about an hour or two away from Mayo.

And she was Killip Class 3. And they called me, and I said, well, I think just transfer her. She is quite high risk of bleeding because of age, history of hypertension, low BMI. And I said, just transfer her and don't give her lytics. And she was Killip Class 3. Well, that might there was a tornado watch. And then 10 minutes later, they called and said, helicopters are grounded, and it's going to be about four hours road transport. And I said, OK, well, then give her a lytic.

And she came and we took her to the lab. The vessel was occluded, it was opened, and then she died the next morning from an intracranial hemorrhage. Now, I show that case and I say, I still would have done the same thing today, because her risk of intracranial bleeding was about 6% to 7%. The other way of looking at it is 93% likelihood that she wouldn't bleed. But she did bleed. But she was Killip Class 3 and we had to do something, and it was going to be four hours before she got to Mayo.

So it's a judgment call. I do think that in general what I think is a reasonable approach is, are you are you going to be able to get the patient to a cath lab within two hours of [INAUDIBLE] presentation? And then you take into account the duration of symptoms. So if the patient has had four hours of symptoms, it's not really going to matter whether you get them to a cath lab within two hours, or two hours 10 minutes, or two hours and 30 minutes. Just transport them.

But when you have someone with a short duration of symptoms, maybe 60 minutes of symptoms, and now you're looking at two to three hours transport time to a cath lab, well, then you've got to weigh up the risks and the benefits. And then someone like that, young, low risk of bleeding, sick, Killip Class 2, anterior infarct or complicated inferior infarct, they've only got 60 minutes of symptoms, and you've now got a two to three hour transport time, I think the guidelines say pharmacoinvasive.

MANDEEP SINGH: Thank you. The only other question I have is, now, as we move forward, you've talked about microvascular dysfunction as one of the prime targets, do you think we should complement the novel strategies, such as microvascular dysfunction, but also focus more on symptom onset to presentation? In other words, educating the public more, or have some resources.

Because we've done everything to shorten the door-to-balloon time, the DIDO times, which are after the patient makes a contact with a medical facility. But we haven't spent so many resources towards educating the public towards early presentation to a medical facility.

BERNARD GERSH: You're absolutely correct. Unfortunately, what little data we have is not very encouraging. Several years ago there are a number of studies performed. One of them was in Gothenburg, Sweden. And they had a massive public education campaign. Present early go straight-- call the ER, and so on, and so on. And what they found in the first three months was the ER was flooded with non-cardiac chest pain.

And three months later, after the campaign died down-- they had this media campaign, a TV campaign-- three months later, everything went back to where it was before. And that's been the experience of others, at least the published data. And that is that educating the public to seek medical attention earlier is incredibly logical. I believe it would make a huge difference. But so far, attempts to do that have failed.

And in the US, I don't know what the figure is, but a large number of patients still drive themselves to hospital and don't call EMS. It's only about 50%, I think, call EMS. I'm not sure of the exact number. But the other part of your comment about microvascular dysfunction, right now the only way I to reduce microvascular dysfunction is to treat earlier. One of the early slides-- one of the first few slides that I showed illustrated that if you had a long symptom-to-balloon time, you had much more microvascular dysfunction than if you had a short symptom-to-balloon time.

All the other attempts to improve microvascular function with multiple different agents, and drugs, and approaches, have so far been blank, had no effect. I mentioned a trial I'm involved in, and that is the role of remote ischemic preconditioning in the ambulance, and its effect on myocardial salvage, and, in turn, microvascular dysfunction. But microvascular dysfunction, quote, reperfusion injury, is still the last frontier, I think, of reperfusion. And after two decades of trials, we're still left with the fact that many things work in animals, but they don't work in patients.

And I think the reason is the long presentation times. I mean, most people that we see are already two hours out.

MANDEEP SINGH: Yeah. So I have one more question before we wind down this excellent presentation. The question is, at what point in time would you not recommend a pharmacoinvasive approach in a patient who is presenting to a non-PCI facility with longer transport times? The participant says, often it's difficult to obtain history of exact timing of onset. Maybe a poor historian. And then the other thing he or she is asking is, what a adjunctive therapy would you recommend with thrombolytics such as heparin, Plavix, et cetera?

BERNARD GERSH: Let me just think about this. First of all, it's a very good question. How do you time the onset of myocardial infarct. And we've all been there. We just don't know. Patient wakes up at 1:00 in the morning, they've got pain, they're restless, they take something, go back to sleep. Wake up again at 4:00 in the morning with more pain, and then eventually at 7:00 o'clock, 8:00 o'clock, go to the emergency room. Did the infarct start at 1:00 in the morning, or-- we don't know.

And I think in my graph that I showed of the curve, I mentioned that one of the variables is stuttering infarction. And I think what is important there is to realize that you may not be able to time the onset of myocardial infarction precisely, and you may not be able to do it, but one thing that-- it's not that reliable, but the presence of Q waves. They have shown in the trial, the STREAM trial, that in terms of outcomes, if you have pathological Q waves at the time of presentation, the likelihood of salvage, of extensive salvage, is much less.

That's quite an important determinant. So I think you have a patient, you're not quite sure of the duration of the infarct, it's a stuttering infarct and they don't have Q waves, they've still got good voltage, ST segments elevated, that means one thing. But if you have someone else, and you're not exactly sure of the duration of time, but they have low voltage, established Q waves, pain--

I mean, all of these patients, if you say to them, do you have any discomfort? I think most patients actually describe chest discomfort that goes on for even into the next day. But when you look at those patients, they're very comfortable. They're reading the paper and they say, yeah, yeah, I've got a little discomfort. Maybe they have a little pericarditis, but they're comfortable. But the patient who has an ongoing infarction is not comfortable. They're diaphoretic.

And I think it's a clinical judgment. So if someone comes in, and they may have infarcted three or four hours ago, they've got Q waves, they've got vague pain, there's no urgency now. Just transfer the patient. And I think you have to make a clinical decision. And you will not, in many patients, have an exact time. It's not necessarily 122 minutes, 118 minutes.

MANDEEP SINGH: And then the adjunctive therapy? So Plavix, is that your go-to drug that you give as thrombolytics.

BERNARD GERSH: Yeah. I think that one of the points I've made is, is there a benefit to ticagrelor? We don't know in this-- I don't think in this situation of reperfusion therapy that we have that data.

MANDEEP SINGH: Yeah, yeah. No, I want to thank you, Bernie, for this excellent presentation. On behalf of Dr. Lloyd, [INAUDIBLE], Gina, and Jeff in media, and from our own department, which you are part of, we want to thank you for being a part of this webinar. Thank you so much. Have a wonderful day.

BERNARD GERSH: Pleasure, thank you.

Cardiovascular Medicine webinar — Reperfusion therapy for STEMI: A case for the pharmacoinvasive approach even in the USA

In this Cardiovascular Medicine webinar, Reperfusion therapy for ST-elevated myocardial infarction (STEMI): A case for the pharmacoinvasive approach even in the USA, Mayo Clinic cardiology experts Bernard J. Gersh, M.B., Ch.B., D.Phil., and Mandeep Singh, M.D., focus on the impact of early reperfusion on infarct size and outcomes with an emphasis on a systems approach in communities that do not have a percutaneous coronary intervention (PCI)-capable catheterization laboratory and consequently rely on rapid transport to a referral hospital with the requisite facilities. The advantages and disadvantages of thrombolysis followed by transport (the "drip and ship" or pharmacoinvasive approach) are discussed, as are barriers to optimizing this therapeutic strategy.

For more information or to refer a patient, visit Mayo Clinic Medical Professionals — Cardiovascular Diseases.


Published

March 12, 2021

Created by

Mayo Clinic

Related Presenters

Mandeep Singh, MD

Mandeep Singh, MD

Cardiologist
Internist
Interventional Cardiologist

View full profile