Ep 15 - Understanding Troponin - Part 2

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Welcome to the St. Emlyn's podcast. I'm Iain Beardsell and I'm Rick Body And this is part two of our Traponing special where we're going to delve even deeper into this protein molecule and how it can help us in the emergency department. Now, as regular readers of the blog and the cardiological and ED literature will know, Rick is a world leader in investigation of high sensitivity Traponing. And that's the topic we're going to tackle today. I've got a list of questions for him.

I'm going to just sit here, ask him everything I hope that you all want to know, and I'm just going to let him go. So, Rick, are you ready? I'm ready. Thanks for that, rather overwhelming introduction. Let's start with so high-sensitive Traponing. Can we just start off by defining what we mean by a high-sensitivity assay and a high-sensitive Traponing? Yeah, so this is probably the most important point to understand, isn't it? High-sensitive

Traponing. It sounds like high-diagnostic sensitivity. And as we touched on the last time, there's a big difference between analytical sensitivity, which is how low are the concentrations at the assay can detect and diagnostic sensitivity, which is about how well does it perform in terms of diagnosing and acute myocardial infarction. High-sensitivity Traponing talks about analytical sensitivity, so with a high-sensitivity Traponing assay, we can detect much lower concentrations of Traponing.

With the previous generations of Traponing, assay, it was an uncommon for us to basically have patients who had undetectable Traponing or positive Traponins because the 99% tail in a reference population, the upper reference limit, for example, the test, was set at the detection limit, so if you had detectable levels, then it was abnormal. With a high-sensitivity Traponing test, we can achieve something rather marvelous and that we can detect Traponing levels in apparently

healthy individuals. In fact, to be labeled as a high-sensitivity Traponing assay, it has to be able to detect Traponing levels in at least half of apparently healthy individuals. So that's the first criterion and assay needs to hit in order to be labeled as high-sensitivity. So let's just go back to that one very briefly. What we're saying there is that everybody, normal people, have Traponing that is detectable in their blood, so we are releasing Traponing from our

cardiac muscles, from our macardium all the time. The reason that we haven't picked it up before was in essence just because the analysers we were using to measure it were not able to do it. They weren't able to see those molecules. That's exactly right, yes. And if probably we had the perfect technology that could detect any Traponing level, probably we'd find that Traponing levels are normally distributed in the population and that we all have a baseline level of Traponing,

but it varies depending on our state of health. So that's the first characteristic for a high analytical sensitivity Traponing in that it has to be present in 50% of a normal population. Are there other factors as well that make a Traponing highly sensitive? Yeah, there's one more criterion that you have to hit and that's about precision. So precision is, as you might expect, about how precise the result is that you see when you get the lab report.

When we get lab results, of course, it's not perfect. If we tested the same sample a number of times, we get slightly different results with any lab test and we can quantify that level of variation with something called the coefficient of variation. So that tells us roughly how much we might expect a single result to vary if we retested that same sample with the same level of Traponing in it.

And what we said, what the experts said was an acceptable coefficient of variation for diagnosing an acute myocardial infarction was 10%, so you need a coefficient of variation of less than 10% at the cutoff for acute myocardial infarction in order to diagnose an acute MI. Unfortunately, the previous generations of assays didn't achieve that level of precision. High sensitivity assays know do, so they have a coefficient of variation of less than 10% at the cutoff.

So this may be something that surprises people. We're doing diagnostic tests all the time, not just Traponins, we're running full blood counts, white cell counts, amylases, we're doing liver function tests. You and E tests, each of these tests have variation if you run them a certain number of times. So if somebody took blood from me right now and they measured my sodium level and they they've repeated that 10 times, they would get 10 different results and the variation between

those results could be quite wide more than 10%. Yeah, that's right, and that's really important to understand. So for example, if you saw two sodium results from the same patient and one of them was one three one and the next one was one three three, you could say, oh, it looks like the sodium is going off, it's heading in the in the right direction, but actually it may not be, it might just be

within the realms of what we call analytical variation. Already I can imagine people listening to this podcast, they're driving in their cars and they felt the need to pull over with this revelation that our testing isn't as accurate as we once thought it was. So we should just let them get the breath back before they restart their cars and restart their journey to work, but it is something that's really important to bear in mind. Number of times with other tests, we talk about the hemoglobin

and people say, oh, the hemoglobin's changed by one gram. Actually, that one gram measurement could, it may not be, but that could just be due to the variation, the analytical variation in the testing. Hopefully everyone's got their breath back, they've restarted the cars, they've pulled safely back

on to the freeway, the motorway, the village lane. Let's get back to troponing. So the high sensitivity to troponing, the high analytical sensitivity, the two things I think you said were, it needs to be detectable in 50% of normal people, normal people with no myocardial disease and it also has to have a coefficient of variation, which is less than 10%. So if you did repeated measurements on the same

person, the same sample, it will never vary the result at the cutoff of more than 10%. Yes, and the 10% roughly varying by 10% is a very rough figure. It's not quite as simple as that, but as a ballpark, it gives you the right idea. So now we understand a bit more about what it means to be a high sensitivity to troponing. I guess we should move on a little bit now and talk about how we can use that

difference in the emergency department. Let's just flick a little bit between analytical sensitivity and diagnostic sensitivity. Can we therefore say that a high sensitivity troponing has also got high diagnostic sensitivity because obviously ruling out disease is something that we're very interested in. Well, the two things are very different. So not necessarily, just because you can detect lower concentrations, doesn't mean you'll get a higher diagnostic sensitivity. So we have to

do research to find out if there is higher diagnostic sensitivity. The research show is that actually high sensitivity assays do have a higher diagnostic sensitivity when we use them, for example, at the time of arrival in the emergency department for patients who have a suspected M.I. Whereas the sensitivity of the older assays might be more like 80, 85%, the sensitivity of a higher sensitivity troponing assay is more like 90 or 92%. And this is because we can detect even smaller

quantities of troponing and we know how much should be in a normal individual. There's actually a really interesting thing here unless, I mean, we can't avoid focusing in on individual assays just to make examples here. So let's focus in on the troponing TSA from Rosh because I think that's quite widely used. It's a high sensitivity troponing TSA. The 99% tile or the cutoff of that assay is 14 nanograms per litre. We can detect levels right down to three nanograms per litre. So being a high

sensitivity assay, we've now got these levels between three and 14 that we can detect. And then normal. The 99% tile is still the 99% tile. So if, you know, with the old one, it was 10 nanograms per litre, now the 99% tile is 14 nanograms per litre. That seems higher and that seems crazy. Doesn't know you'd expect the higher sensitivity assay to have a lower cutoff for diagnosing a my. And it's

higher. So how does that work? Well, actually, what we found is with the higher sensitivity troponing assay, particularly troponing T, the apparent results that we get from the lab are higher than they used to be with the old troponing assays. So let's say we have the same sample. Let's say we tested this sample using the standard troponing TSA and we got the level back as 10 nanograms per litre. That's right at the cutoff, the 99% tile. Now we remeasure it using the high sensitivity

troponing TSA. What would the level be? You might say, well, it'll be 14 because that's 99% tile. In fact, it won't. The reading we get from the higher sensitivity assay is even higher, about 35 nanograms per litre. And it's the same sample. So 35 nanograms per litre is the reading that you get with the higher sensitivity assay, whereas 10 nanograms per litre was the reading you got with the previous generation of assay. What that means is you've got all of these extra positive

results. The levels of between 10 and 35 using the old assay that were previously normal and are now abnormal above the cutoff. So you get more positives. When you're getting more positives, you're effectively, what you're effectively doing is you've lowered the diagnostic threshold. And when you lower the diagnostic threshold, you're going to higher diagnostic sensitivity at the expense of specificity. So with each of these tests, it's always a balance from a diagnostic

point of view between sensitivity and specificity. Now by chance, the high sensitivity and a litre called sensitive depotonin, I think we're really using to focus in on early rule outs. So our diagnostic sensitivity is what's important. Do we have to have a big compromise with specificity and sensitivity? We said in our last episode that if you've got a positive depotonin at patient arrival, then that was about 90% specific. Where are we with specificity for

the first sample using a high sensitivity depotonin? So specificity is much lower. Again, it varies a little bit with the assays and the Abbott depotonin assays seems to be a bit more specific than the rush depotonin assay, just using a single measurement on arrival. But the specificity, let's say, we're talked about the rush assay, the depotonin assay. Let's look, let's talk about that. The specificity of that is much lower. I think it's around about 70%.

Sometimes it's a little bit more easy to understand that as a positive predictive value, as I mentioned briefly in the last podcast. If you've got a patient with a spectacardia chest pain, a positive high sensitivity depotonin, the postoperability or the positive predictive value of that is only 50%. So only half of those patients with a positive depotonin ass that are

having an acute myocardial infarction. It is important to appreciate that when we use depotonin on arrival in the emergency department, a positive result doesn't necessarily mean that the patient's having an acute amine. And a negative depotonin on arrival doesn't necessarily mean that the patient can be ruled out. So we take into account a pre-test probability. Now we said in the last podcast that depotonin is used as a reference standard for myocardial infarction.

Can we use high sensitivity depotonin in the same way as a reference standard for myocardial infarction? The universal definition of myocardial infarction states that you need a rise and or fall of depotonin to above the 90% tile. First of all, just taking the depotonin results. If you got a depotonin of 15 and you develop to rise and or fall of the depotonin, then you potentially are eligible for a diagnosis of an acute myocardial infarction.

And yes, you could use that high sensitivity depotonin as a reference standard. In fact, it's going to be a more sensitive reference standard than the previous generation assays, because we'll be able to diagnose acute myocardial infarctions that we were never able to diagnose before. In fact, the apparent incidence of acute myocardial infarction would go up by about

a third using high sensitivity assays. You don't just need the depotonin though, so to diagnose and acute myocardial infarction, you need the rise and or fall of depotonin, but you need the correct clinical context as well. And that's a really important point to have a home really. So, Rick, we've got this high analytical sensitivity test. We've got this high diagnostic sensitivity test. This all sounds great. We're getting newer technology that measures ever lower

levels of depotonin. It's a way in which we can incorporate this into our clinical work that may help us both facilitate patients through the emergency department quicker, but also make us more accurate in our diagnosis. Yeah, and I think that's the key question, isn't it? It's all very well saying that the sensitivity of these neutroponin tests on arrival is slightly higher than the previous generation assays, but it can't rule you out,

and nor does it rule you in. So, what we want to know is emergency positions is how does this actually help us? And how does it change what we do? How can we change our protocols to accommodate high sensitivity depotonin assays? The most attractive thing potentially about high sensitivity depotonin is you can bring forward the time at which you rule out and acute myocardial infarction using serial sampling. So, there's been lots of talk about doing depotonins three hours after

arrival instead of waiting for six hours after arrival. Can you do that? Well, there's some good evidence to suggest that you might be able to do that. The best is using the Abbott High Sensitivity Depotonin assay, a paper published in JAMA by Moolers Group. I suggested that the Abbott High Sensitivity Depoton assay had a sensitivity of 98.1% for acute myocardial infarction when tested at zero and three hours. So, it's not bad, it's not perfect, but it's not bad. And there's a little

bit of limited evidence that you can do the same thing with the rush assay as well. There was an abstract published in circulation, but it suggested that it has a quite high diagnostic sensitivity if you do depotonins at zero and three hours. And potentially, that's how it will really help us in the

emergency department. So, we're able to bring forward that second test instead of waiting either six hours after arrival or as we do in the UK 10 hours, 12 hours after the onset of pain, we can bring our testing forward, get the patients through the department quicker, and be reassured that we're sending them home safely without them having myocardial damage. Yeah, and that's a potential attraction of high sensitivity depotonins. I think it's still

early days. We're still in the process of revising our protocols and seeing how it goes. You know, there's a real challenge in doing a zero and three hour depotonin interpreting the results and letting patients go home safely within the four hour emergency department journey. It may not be feasible. We'll wait and see. And we've described before and Simon talked about in the past and he talked about it smack last year, this idea of early adopters and change.

Are you an earlier adopter? You surely at the forefront of troponin testing. Are you going to be moving towards a high sensitivity depotonin? Have you got some sort of protocol that you would be using? I really enjoy Simon's talk at smack old about, you know, when to change because that's a really key question. I do think it's important that we are open to being early adopters if the evidence is sufficient to make the change. The question is, is the evidence sufficient to make the change in this

regard? I'm a little bit limited by what I can say because I'm working with nice on the recommendations for the use of high sensitivity depotonin in practice and that won't publish until October. And most people will have probably seen the draft guidance on the website. We suggest that we might be moving towards a zero and three hour troponin specifically when we use high sensitivity depotonin

assays. That's the abit high sensitivity depotonin assay or the rushed depotonin assay. I guess if you want to implement one of those protocols, you have to know which assay you're loves using because it has to be one of those assays. So we've got these protocols that are being developed. I know there's different groups publishing different ideas. Everybody needs this. The emergency departments throughout

the UK and worldwide are pressurised with too many patients, too much to do. This is hugely attractive. People like yourself are working very hard to find a safe way that we can use these. If we just think a little bit, we've talked about a zero and three hour protocol. Now other protocols also involve deltas. Can you just explain a little bit about what deltas are? Yes, so what's really important

when we're interpreting depotonin levels is that we don't just take account of a single value. We need to know whether the levels rising or falling because if in the universal definition of acute myocardial infarction that I mentioned before, you have to have a rise and or fall of depotonin. The big question is what is a rise and or fall of depotonin? How much change does that have to be? And the answer will be different for the different depotonin assays. So again, you've got to know which

assay your love is using. Traditionally, we always said that a 20% change between the between the test results is significant and can be consistent with an acute myocardial infarction. When you look at where the evidence for that came from, there isn't any. I can't find any. It seems to have been arbitrary based on the analytical characteristics of the tests. And there are some potential drawbacks to using that 20% delta. It's a relative change, so 20% is a relative delta.

What we mean is we need the first level to change by 20% in order to enable it a significant. Imagine what that means. So if you had a patient who started off with a high-centred depotonin T level of 10 or 11 nanograms per liter and it goes up to 15 nanograms per liter. Well, that's more than a 20% change. So we've labeled them potentially as having had an acute myocardial infarction, but actually the absolute change is only four or five nanograms per liter. And that could easily be

analytical variation. It could be that you've just tested the same sample twice and got different results because of the limitations of the test. On the other hand, you've got a patient who starts off with a tropone of 2000 nanograms per liter, massive tropone elevation, and then you retest it. And it's gone up by 100 nanograms per liter to 2,100 nanograms per liter. Well, that's pretty massive. I mean, that patient's had a huge MI, but they haven't got a 20% delta. It's only 5%. And they would

be... we'd tell them that they haven't had an acute myocardial infarction. Well, that's just still it. Because of that, there's been a move towards looking at absolute delta. So look at the absolute change. And there's some really good data again from Christian Moulin, Matthias Moulin looking at absolute

versus relative deltas. And absolute deltas seem to outperform the relatives. With the rushed tropone and TSA, it seems that a change of anything more than 9.2 nanograms per liter, or because we report in whole numbers, anything more than 10, or at least 10 nanograms per liter, is a significant change. And that's probably the direction that we're going to. So we have to combine both the delta, which is the change in tropone in between the two measurements, but also the

absolute cutoff. So you mentioned there a patient who comes in with an initial tropone in of 10, nanograms per liter on the rush, I say. And then they go to 15. Obviously, 15 is above the cutoff of 14. So we would rule them in. We would keep them in hospital and say they need further testing, regardless of the delta. So it's a combination of the two. One of the ones I'd be interested in your thoughts on is, let's just take that second result down a little bit. So they come in, they have their

first test, it's at 10 nanograms per liter. The next test done three hours later is 13 nanograms per liter. Now that is more than a 20% rise, but they're still below the reference range. Now they've had two negative results, but the delta is 20%. It's more than 20%. What would you do with those? Well, so there it's really important to understand the, what you might expect in terms of analytical variation. So that change is only three nanograms per liter and we know that that level at the test

isn't perfect. So it could have just been the fault of the test and you might not really have seen a rise, but it may just be that it looks like it. There might have been little amounts of hemolysis in the samples, differences in the way the out samples handled, for example, that could account for it. So it's probably not significant. If you worried about it, if it's rising up below the normal range, then I think the safest thing to do is to repeat the test.

This would be particularly important. For example, let's say we saw a patient with an initial trope on in a four and then it went up to 13 at three hours. Would you send that patient at home and rule them out? Well, probably not because that's a much more substantial rise of nine nanograms per liter. You probably want to repeat that test again later to see if it rises above the cutoff.

So all of this is coming down to the idea that we have this new test. New test saw is exciting, especially when it can help us rule out disease and help us rule out disease quicker, but we need to be smart in the way that we're using it. We need to make sure that we think about the values. People will be setting up guidelines, protocols, and I will come out with some advice,

but it's always related to the clinical context. I think that's a really important point. I mentioned in the first podcast on Traponin, the specificity of the old tests was quite high, you know, it's in the 90s. So, you know, we'd see a positive result and we'd leap to the conclusion that it was an acute myocardial infarction. With the new tests, it's much, much less sad. You can't rely on that. And I think that what it forces us to do is to think really hard about the clinical context

and what's going on. And also about the results themselves, what's the change between them, and how do we interpret that? Is it analytical variation? Do we need to do another sample to just make sure that this isn't rising? It's all about doing some thinking around the result and not just having a spinal reflex and reacting to negative or positive Traponin as a blanket rule in and rule out.

And hopefully this podcast will help people understand a little bit the background to how we get these tests, where they come from, so they'll be able to use it in the clinical context. Now I mentioned at my department that I was chatting to you, Rick, and some people came up with some questions that they wanted to know about Traponin. Hopefully people also be able to write in

onto the blog post. I know that you're really happy to take questions about this, and I'm sure there will be some, but just one or two things that people from my hospital wanted to ask you if you don't mind. So one of the questions that somebody wanted to ask was we're doing more and more tests at the front door when people first arrive, hoping this will speed patients through the department. We've talked about clinical context, but sometimes we're compromising that for efficiency or so

called efficiency. This means that we're going to be doing Traponin's on people whose pre-test probability is low. What do we do with a patient where we get an incidental rise in Traponin? They've come in, they've fractured the necophemate, they had a mechanical fall, some well-meaning person does a high-centage opponent, and it comes back not negative. What do we do now?

So that's a really interesting question, and I think what's really important is that we don't overreact and call cardiology and request a whole battery of invasive investigations or treat the patient with anti-platelets, anti-thrombotics, because we're going to expose them to unnecessary risk. The post-test probability of a positive Traponin in that patient is going to be extremely low. We've not ruled anything in. In fact, we're closer to ruling it out just because the pre-test probability

is so low. So if you really do think that this might have been something that you've found incidentally on the Traponin level that you hadn't thought about, then maybe you'll repeat it later and see what's happening to that Traponin level. If it appears that that Traponin is totally in context with the unicorns with a patient's baseline condition, perhaps we know a bit about

their background history and some things that we would expect to raise that Traponin. For example, age, older patients are much more likely to have a positive Traponin that's just above the cut-up. In no circumstances, we'd relax a little bit and think, well, actually this is just a Traponin level that I would expect for that particular patient. The best evidence we've got for that is from Paul Collins in its eight Georgia's. He did a fantastic study looking at the reference range

of population from general practice. What he did is he ran the high-centred Traponin T-test in a load of these apparently healthy people. He gave them questionnaires to find out if they had cardiovascular comorbidities or if they took cardiac medications. He got an echo on them all, he ran a BNP on them all, and then he developed a derived at the reference range. So, remember for the Rastroponin T, the manufacturer tells us that the 99% tail is 14 nanograms per litre.

If Paul screened out all the patients with abnormal BNP abnormal echo and no significant comorbidities, he found that the 99% tail was 14 nanograms per litre, exactly what the manufacturer says. But when he included all comas, all of the patients, regardless of whether they had LV dysfunction, comorbidities, etc, the reference range went right up the 99% tail was more like 35, 40 nanograms per litre. And that tells us the levels that we might expect in patients who have

conditions like LV dysfunction, renal impairment, cardiac risk factors. So, we can use that to interpret the level that we see in an individual patient and determine whether it's out of context for the patient that we're treating. So again, I think what we're trying to say is that all of this has to be taken in context. I know our cardiological colleagues, they're getting slammed at the moment with all sorts of calls to them from the emergency department and sometimes I think they must feel

like troponinologists. Patient has positive troponin, ring cardiology, patient that has positive troponin must go to CCU. But what we're trying to reiterate, and it's not just because we're trying to make friends with cardiology, we as emergent physicians have a responsibility to understand the testing we're doing and put it into the context of the patient that we're seeing. So a positive troponin doesn't necessarily mean a knee-jerk response of booking a bed on CCU and referring them to

cardiology. So, a couple other questions if you don't mind Rick. So, a very quick one, which I think we've sort of covered already. Why is it patients with stroke get a positive troponin? So, the interesting thing is that is cardiac specific. So, you're still getting myocardial damage and there are lots of reasons why a patient with a stroke, for example, might get myocardial injury. Baisyl spasm is the most likely mechanism. So, typically, for example, a patient with a sub-righton

head hemorrhage, the classics are in that. You might see a patient with a sudden onset headache, photophobic neck stiffness, you do a CT, you see a sub-righton head hemorrhage, someone checks an ECJ and it shows ST elevation. And the troponins will be high because concurrently with what's going on in a CNS, you get vasospasm in the coronary circulation and that can lead to myocardial injury. And that's the most likely mechanism to be seen. So, I talk about again, myocardial injury, not my

cardiomypharaction. Now, we touched on analyzer's analytical sensitivity earlier. You described in our previous podcast these massive machines that are required to measure troponin accurately and these high sensitivity assays are even more accurate. So, I'm presuming this is why we don't have a point of care test. Yeah, hopefully one day we will, but they're not quite reached the requirements to be high

sensitivity and they're actually quite a long way off. So, Rick, that's been an excellent roundup about high sensitivity troponin. We've covered why it's different to our regular troponins, how it's measured, some of the very interesting points about analytical sensitivity, how we can use it in the clinical context. I'm certain this will bring out some more questions from people listening and please do write in to the blog post and email us if you've got any questions you'd like to ask, Rick.

Rick, I know that there's a nice panel that in the UK, they're the group of experts who recommend what we should be doing in the future. I know you're part of that panel. I'm sure we'll have you back in to talk about that and we may even do a little podcast about the draft guidance that's come out recently. But for now, just a big thank you from me, thank you from us all first, sharing some of that expertise that you've gained over years of researching into this. It's been

fascinating talking to you. I've learnt so much and I hope our listeners have too. But from now from the St. Emelon's podcast, we'll say goodbye.